The Rhineland Biopatent Blog



The times they are a’changing – particularly in the Biopatent discipline. Biopatent professionals live in a quickly developing world, which is sometimes hard to keep pace with. Michalski · Huettermann & Partner Patent Attorneys have decided to produce relief to this situation, and are proud to present a new information service related to Patent issues in Biotechnology. The news in this Blog issue on an irregular basis in order to provide information with respect to actual events, as well as in-depth-analyses of long-term developments. Patent Attorneys from our firm explain the meaning of recent developments and decisions affecting the Biopatent community, and provide expert insight into what's going on behind the scenes.



It’s the enablement, stupid !
DC Delaware judge overturns decision by own jury and revokes Amgen’s PCSK9 patents
13 September 2019 (3/2019) The Amgen/Sanofi debate is a frequent guest in this gazette (see issues 4/2016, 7/2017, 2/2018 and 3/2018). 
In a nutshell, Amgen and Sanofi both have an anti PCSK9 antibody that is used to treat hyperlipidemia. Amgen has, both in Europe and the US, patents that protect the antibody by the epitope it binds on PCSK9 (so-called epitope based claims), which, surprise, is also the epitope that Sanofi’s antibody binds to. 
And, surprise, Amgen sued Sanofi for patent infringement, demanding damages and injunction both in the US and Germany. 
The Delaware District Court (DC Delaware), in a jury decision, declared, on January 3, 2017, the patents valid and confirmed that Sanofi’s antibody would fall under the scope thereof. It also issued an injunction against Sanofi.
On appeal, the Court of Appeals for the Federal Circuit (CAFC) vacated the injunction (October 5, 2017), and then remanded the case back to the first instance, ordering the court to better instruct the jury about how to apply the proper test on validity of these types of claims.
Essentially, the problem was that epitope based claims have an inherent written description problem. Wthile they generally describe the epitope in great detail, they often describe only a few antibodies. However, once granted, the scope of such claims covers more than only those antibodies that have been described.
Hence, a right balance must be found in such way that a sufficient number of species (=described antibodies) is required to justify genus protection. 
When the CAFC decision to remand the case to the first instance came out, epitope based claims were deemed practically dead at least in the US, as for example evidenced in a panel discussion at the BioConvention 2018 in Boston, to which the author of this article contributed.
However, in a decision of February 25, 2019, the Jury of DC Delaware came to the conclusion that at least some of Amgen’s claims would even stand the higher bar on written description as suggested by the CAFC. Surprise, Sanofi’s product still fell under the scope of these claims. 
Hence, all of a sudden, epitope based claims were back from the oxygen tent.
Sanofi, in response, filed a request for Judgement as a matter of law (JMOL) – meaning, they wanted a judge to overturn the Jury decision. 
JMOL can be admissible if the court finds that a reasonable jury would not have legally sufficient evidentiary basis to find for a party on an issue – a requirement which, regarding a matter as complicated as the patentability of epitope based antibody claims – seems likely fulfilled.
DC Delaware Judge Andrews accepted the case an reexamined the Jury´s decision for written description and enablement – which, as we all know, are separate patentability requirements under US law. 
In his opinion, which issued August 28, 2019, Judge Andrews declared the patents invalid – hence, back into the emergency room. With regard to written description, he confirmed the Jury decision, basically on the finding that Amgen’s patents would pass the “representative species test”, because a) the use of AA sequences as a measure to determine whether there would be sufficient species would not be appropriate, b) still, there would be sufficient AA sequence similarity between Amgens’s and Sanofi’s Antibody, because Amgen would have disclosed 8 different families of blocking antibodies (while, in the AbbVie vs Janssen decision (759 F.3d 1285 (Fed. Cir. 2014) all antibodies AbbVie had disclosed in their patent were derived from a clone called Joe-9), and c) Amgen had also shown that the different antibodies discloses would all bind to different residues of PSCK9, though and the “sweet spot” of the target , i.e., the epitope referred to in the claims by AA residue reference. Hence, though likely to be appealed, this decision provides some drafting guidance for future applications, so as to meet the written description requirement in epitope based claims.
With regard to enablement, Judge Andrews first emphasized that, in order to meet this requirement, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.
In this regard, Sanofi referred, inter alia, to the language of claim 19 of Amgen’s 8,829,165 patent (“antibody which binds to at least two of the residues R1 – R13“), and argued that it would be impossible to make an antibody that binds to only two AA residues without touching any other of the thirteen residues – and argument which, no surprise, did not convince Judge Andrews.
However, the Judge found that, in view of the facts that (i) the number of antibodies falling within the claim scope is in the millions, that (ii) substitution of amino acids in a sequence may have unpredictable effects on antibody function, and (iii) even despite the routine techniques available to identify antibodies within the claim scope, it would appear that a person of ordinary skill in the art would still be required to do essentially the same amount of work as the inventors of the patents-in-suit. 
Judge Andrews herein referred to the same Court’s decision MorphoSys vs Janssen  (358 F. Supp 3d 354; D Del 2019), that issued earlier this year, on January 25. (in which case the parties settled, so an appeal was not filed). 
In fact, Judge Andrews explained, the specification would not provide guidance on how to predict the effect of the sequence on the function of the antibody. The "roadmap" disclosed by the patents would almost be exactly the same as the patentee's initial research process to discover the twenty-six disclosed antibodies. As a consequence, he declared the patents invalid for lack of enablement – and, as a consequence, also permanently vacated the injunction. 
The underlying arguments are remarkable, as Judge Andrews ignores the idea that the key achievement on which the patents would settle could not be the actual antibodies, but the identification and characterization of a functional epitope, binding of which has the desired effect (while blocking other stretches of the target would not). 
Ii seems likely that Amgen will appeal this decision, and we are eager to see what the Federal Circuit does with it, in particular because the latter has, recently, mostly dealt with written description father than enablement of antibody patents. 
In decision Chiron vs Genentech (363 F.3d 1247, 1254-1256 (Fed. Cir. 2004), the CFAC found the asserted claims invalid because the disclosure failed to provide a specific and useful teaching of all antibodies within the scope of the claim – however, this decision dates from 2004.
Because the decision Judge Andrews relies on has not made it into appeal, there is a chance that the Federal Circuit will create clarity here. 
Is there public need for “still another” drug ?
German Supreme Court denies compulsory license
13 September 2019 (3/2019) As already discussed in this Gazette, much of the public interest related to the Sanofi vs Amgen debate focuses on the question whether, even with a valid drug patent, an injunction against a competing drug product is justified. 
The injunction against Sanofi’s Praluent, that came with the DC Delaware Jury’s first decision, received a very critical echo in the US, because there had already been patients who had a prescription for Praluent, and who would have been deprived them of their actual heart medication. 
Traditionally, US courts are inclined to not award injunctions against approved therapeutic drugs, because this would harm the public interest. Instead, damages and license payments are usually awarded (or agreed upon in respective settlements). 
Rachel Sachs, an associate professor of law at Washington University in St. Louis has been cited that it would be “strange for a judge to take one product off the market when there are patients on the medicine already”.
In Germany, Sanofi has been sued by Amgen for violation of their European patent EP2215124B1 before the District Court in Duesseldorf (OLG). Amgen demanded, inter alia, an injunction and damages. 
In response, Sanofi filed an action at the German Federal Patent Court (BPatG) against Amgen’s European Patent EP2215124B1 to order a compulsory license under reasonable royalties. Further, Sanofi demanded a preliminary order to award such license.
After an intermediate stay, the District Court resumed the infringement proceedings and issued an injunction against Sanofi on July 11, 2019. 
Sanofi filed an appeal and then issued a press release according to which the appeal court would have stayed the injunction, allowing further marketing of Praluent. However, said information seems to have been incorrect, as Praluent is actually not available on the German market. 
Regarding the compulsory license case, the BPatG denied Sanofi’s request. Inter alia, the Court found that Sanofi had not sufficiently demonstrated that there was a public interest in the further free availability of Praluent, as Sanofi had failed to make convincing arguments that other products on the market - in this case, Amgen’s Repatha, did not possess the (particular) therapeutic properties of Praluent in equal measure. 
Sanofi appealed to the Federal Supreme Court (BGH), but the latter rejected the appeal on June 4, 2019. 
The Court found that Sanofi had not sufficiently, and not early enough, tried to obtain a license from Amgen, as required under § 24 of the German Patent Act. Further, Sanofi had only offered a very low royalty rate in their belated letter to Sanofi. 
Wisely, Amgen did not completely reject the request, but replied (wisely because, otherwise the BGH may have decided differently), yet Sanofi did not react on Amgen’s reply, but simply waited for the BPatG’s decision. A further letter from Sanofi sent during the appeal proceedings was not considered a serious effort to reach a mutual agreement.
Like the BPatG, the BGH also denied a public interest in the demanded compulsory license. 
The main reason for this was the lack of credibility that Praluent offers any patient benefit over Repatha, in terms of mortality. Both drugs were shown to reduce the risk of a major cardiovascular event by about 15%. Since this significant pharmacological effect is achieved by both antibodies, it alone could not justify a public interest in a compulsory license.
Although according to the results of a clinical study, fewer patients in Praluent group had suffered cardiac arrhythmia or died of cardiovascular disease than in the control group, these results were deemed statistically insignificant.
Also, Praluent had no further indication beyond the indications Repatha is approved for
Finally, the BGH did even not consider the possibility of dosing Praluent lower than Repatha sufficient to justify public interest in a compulsory license.
Note that this decision only referred to Sanofi’s request for a preliminary order to award a compulsory license. 
However, the final determination of the merits of the case is still pending. 
CRISPR Cas dispute flares up again
USPTO initiates new interference
29 July 2019 (2/2019) In a recent press release, MPEG LA, the company that is well known for patent pools in the telecom industry. but is also in a process of establishing a pool for CRISPR Cas patents, has summarized recent developments in the ongoing patent debate.
One of the reasons for said press release is the announcement of Broad Institute and MilliporeSigma to offer joint licenses for their respective CRISPR Cas  patent portfolios – a step which came unexpected because already in 2017, Broad has committed itself to  discussions to contribute to the patent pool coordinated by MPEG LA. 
The new coalition between Broad and MilliporeSigma does not come surprising though. Already a few years ago, Sigma Aldrich mentioned, on their website, that the CRISPR Cas Kit products Sigma was offering for sale then were covered under a license between the Board Institute and Sigma Aldrich, including, inter alia, Broad’s US patent 8,697,359.
Another event that may have triggered MPEG LA’s press release is the fact that the Patent Trial And Appeal Board (PTAB) of the USPTO has initiated on June 24, 2019, on its own motion, a new interference (No. 106,115) against a set of patents and patent applications assigned to Broad Institute (US8697359 et al.) based on a series of patent applications assigned to  University of California (15/947,680 et al.). 
This move came unexpected, too, because the earlier interference initiated by UC Berkeley (covered repeatedly in this Gazette) was finally decided on September 10, 2018. 
The Court of Appeals of the Federal Circuit (CAFC) confirmed a decision of the PTAB of 2017, in which the latter denied that Broad’s patent portfolio covering CRISPR Cas9 technologies would interfere with UC Berkeley’s earlier patent portfolio, covering similar subject matter (see issue 1/2018 of this Gazette). 
MilliporeSigma has now come to Broad’s aide and filed a petition to the USPTO on July 19, 2019 in which it demanded declaration of a parallel interference against UC Berkeley, based on MilliporeSigma’s applications 15/188,911; 15/188,924 and 15/456,204 (the “Chen” portfolio).
In their press release, MPEG LA appeals to the parties to settle their disputes and contribute to the suggested patent pool, stating that “among all the parties involved in CRISPR patent licensing, MPEG LA is unique in its independence and neutrality”, and would hence be able to ”maximize the benefits of CRISPR, as the market needs a patent pool option in which all stakeholders participate and the market’s confusion and uncertainty concerning”. 
This is indeed an honorable approach.
Yet, in a conflict situation thus complex, the prospects of this initiative remain difficult.
CRISPR Cas in  Diagnostic applications
Is a new patent war looming ?
29 July 2019 (2/2019) You know that CRISPR Cas is a powerful tool for genome editing, and, as a frequent reader of this Gazette, subject of a multilateral patent dispute.
Now, CRISPR Cas has also become a tool for advancing diagnostics – and it may happen that we all experience a déjà vu, i.e., a new patent battle. 
It’s all about CRISPR Cas12a, which uses a pathogen specific guide RNA. In a sample to be tested, an isothermal recombinase polymerase amplification (RPA) is carried out, and then Cas12a is added together with its guide RNA. If present, Cas12a finds its target sequences and starts chopping it – together with nearby ssDNA- fluorophore/quencher probes that were added to then reaction mix, and are unspecifically cleaved. Increase of fluorescence hence signals presence of the pathogen. 
The technology, called DETECTR, has been developed by Mammoth Biosciences, which is a spinoff from UC Berkeley and, has licensed the technology from the lab of Jennifer Doudna.
A similar technology, using Cas13 (C2c2) instead (which cuts RNA rather than DNA), is called SHERLOCK, and has been developed by a group from Broad Institute in Boston, based on Feng Zhang’s IP. 
(Wait a minute: Zhang, Doudna – do these names sound familiar ?)
Both approaches are highly sensitive and specific, and can be used in items as simple as mere paper strips. They hence hold great promise in particular when it comes to the diagnosis of viral diseases in less developed countries, like Zika, Lassa  and Dengue. 
While both groups have declared to make the technology available as a scientific platform in particular in the developing world, the situation sparks memories to the current patent battle in CRISPR Cas9. 
Another name for Mammouth’s Cas12a is Cpf1, which Broad filed for patent in 2015 (WO2016205711A1 et al.), and later licensed to Editas, the spin-off cofounded by Feng Zhang. 
It is so far not clear whether Mammouth’s decision for Cas12a will interfere with   Broad’s patent estate, meaning whether or not the latter also covers applications like diagnostics – rest assured, we are working on it. 
New York professor Jacob Sherkow, who has frequently commented on the CRISPR Cas dispute, has commented that “a similar, almost mirror-image scenario” would actually be possible. 
We will wait. And see. And report. 
EPO Opposition Division revokes Broad’s 2nd CRISPR Patent
failed priority claim keeps being a problem
22 February 2019 (1/2019) Last week, on February 14, 2019, the 2nd patent out of Broad Institute’s CRISPR Cas9 patent family was revoked. The Patent, EP2784162B1 had the following independent claim:
1. An engineered, non-naturally occurring Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising:
a) a first regulatory element operably linked to one or more nucleotide sequences encoding one or more CRISPR-Cas system polynucleotide sequences comprising a guide sequence, a tracr RNA, and a tracr mate sequence, wherein the guide sequence hybridizes with one or more target sequences in polynucleotide loci in a eukaryotic cell, 
b) a second regulatory element operably linked to a nucleotide sequence encoding a Type II Cas9 protein,
wherein components (a) and (b) are located on same or different vectors of the system,
wherein the CRISPR-Cas system comprises two or more nuclear localization signals (NLSs) expressed with the nucleotide sequence encoding the Cas9 protein,
whereby the one or more guide sequences target the one or more polynucleotide loci in a eukaryotic cell and the Cas9 protein cleaves the one or more polynucleotide loci, whereby the sequence of the one or more polynucleotide loci is modified.
The patent was opposed by 8 opponents. In the summons to oral proceedings, the Opposition Division had already declared that it would adopt the preliminary position that the priority claim is invalid, for the same reasons as in Broad’s earlier patent from the same family, EP2771468B1 (we have reported on this case, too). 
In a nutshell, inventor Marraffini, who was a co-applicant of inter alia the oldest priority application, had not transferred his priority rights to the applicants of the PCT, Broad Institute, MIT and Harvard University, but to Rockefeller University.
Due to the resulting loss of the priority claim, novelty-destroying prior art published in between became applicable. The Opposition Division maintained its position regarding the loss of the priority claim, despite several experts who opined that the validity of the priority claim should be subject to the legal provisions of the country of origin (i.e., the USA).
We have discussed the underling legal problem in two articles (J Biotechnol. 2018 Jan 10;265:86-92, and Lles Nouvelles, Volume LIII No. 2, June 2018). Please send us an email if you would like to have copies thereof.
The oral proceedings against Broad’s second patent lasted two days, after which the patent was revoked in its entirety, despite >35 auxiliary requests the patent proprietor had submitted. 
The very same day, Broad filed an appeal against this decision.
As already discussed, the failure of the priority claim will likely affect Broad’s other EP family members, although Broad may be able to restore novelty over the intermediate art by relying on claim features which are disclosed in the underlying PCT and confer novelty over the intermediate art. 
And, as discussed in this Gazette, Issue 5/2017, the corresponding PCT application Rockefeller University has filed with Broad Institute, MIT and Harvard University as co-applicants could be the key to regain lost territory, because this family does not have the priority problem discussed above.
European Commission plans major revision of the SPC Regulation
After patent expiry, production of SPC protected drugs for export could become legal
The European Commission has recently announced plans to effect an amendment to the SPC regulation, by introducing a Supplemental Protection Certificate (SPC) manufacturing waiver.1 The suggested changes are intended to improve the business opportunities for EU-based generic and biosimilar companies in view of an alleged competitive disadvantage vis-à-vis their overseas counterparts.
The proposal would allow EU-based companies to produce and store generic or biosimilar products during the SPC term of a branded drug, provided this is done for the purpose of exporting that generic or biosimilar to a non-EU market where protection has expired or never existed.
There is hence quite some conflict potential in the proposal, although we have seen in the past years that the borders between originators and generic/biosimilar companies have blurred, with more and more originators acquiring a generic/biosimilar shop (Novartis/Sandoz, Pfizer/Hospira) or developing a biosimilar business themselves (Amgen). We will discuss this topic at the 11th Rhineland Biopatent Forum, which has been scheduled for June 6, 2019. See our “save the date” information in the “from our firm”-section of this Issue.
1Proposal for a regulation of the European Parliament and of the Council amending Regulation (EC) No 469/2009
New battlefronts in the adalimumab patent epic
how a biosimilar company becomes the prey of another biosimilar company
22 February 2019 (1/2019) More than one time we have discussed new developments in the adalimumab patent battles. 
In issue 8/2017 of this Gazette, we reported that Amgen, who is the maker of the adalimumab biosimilar AMGEVITA®/ AMJEVITA®, settled with AbbVie, the maker of world’s blockbuster No 1, the anti TNFα antibody HUMIRA®, and holder of a large patent portfolio protecting the drug, its indications, dosages and formulations. 
See our article in Human Antibodies 25, which discusses AbbVie’s patent strategy to protect Humira from biosimilar competition. Please ask for a copy here.
Now, this does not mean that Amgen is out of the crosshairs of adalimumab IP stakeholders. 
On January 28, 2019, US company Coherus BioSciences announced that it has become the latest adalimumab biosimilar developer to settle with AbbVie. Under the agreed terms, Coherus’ product, which is not yet approved, will be able to launch in the United States on December 15, 2023.
But that’s not all. Coherus further announced that it has sued Amgen for infringement of its adalimumab formulation patents US 10,155,039, 10,159,732, and 10,159,733.  Although Amgen’s Amjevita is not yet available in the United States, it is already on the market in Europe, and Coherus claims that the production in the US would infringe their respective patents. Coherus has demanded damages and an injunction. 
In fact. Amgen’s formulation differs from the formulation of Humira, as it has the following recipe:
• 40 mg/0.8 ml adalimumab
• 36 mg sucrose
• 0.4 mg polysorbate 80
• 0.24 mg glacial acetic acid
• NaOH for pH adjustment to 5.2 
Coherus’ patents have the following independent claims: 
1. A stable aqueous pharmaceutical composition comprising:
a) adalimumab;
b) a buffer;
c) polysorbate 80; and
d) a sugar,
wherein the composition is free of i) mannitol, ii) citrate and phosphate buffers, and iii) sodium chloride and wherein the composition has a pH of about 5 to about 6. (US10155039)
1. A stable aqueous pharmaceutical composition comprising:
i) adalimumab;
ii) a buffer; and
iii) a stabilizer;
wherein the composition is free of mannitol and has a pH of about 5 to about 6. (US10159732)
1. A stable aqueous pharmaceutical composition comprising:
i) adalimumab;
ii) a single buffer;
iii) a surfactant; and
iv) a sugar,
wherein the composition is free of mannitol and has a pH of about 5 to about 6. (US10159733)
It seems that the common feature of these claims is that they are “free of” mannitol or the citrate/phosphate buffer as provided in the HUMIRA formulation. 
Not very innovative, one might think, considering the relatively late priority date of this family (7 Sept 2012).
See again our article in Human Antibodies 25, for different patents claiming alternative adalimumab formulations. 
Generally, this case shows the shift that is currently taking place in the biologics filed. Once a biologic is off-patent, the IP disputes are shifting from originator vs biosimilar to biosimilar vs biosimilar. 
This development has so far not been seen in the small molecule business, where the battlefronts are still between originators and generics. 
And why is this so? Maybe, because there is probably more science in making a biosimilar than there is in making a small molecular generic. 
Board of Appeal declares Rule 28 (2) EPC invalid
EPO’s jurisdiction takes sweet revenge
On 5 December 2018, the Board of Appeal 3.3.04 issued a groundbreaking decision - T1063/18 – in which it declared Rule 28 (2) EPC as to not comply with Art. 53 (b) EPC. The case relates to the long-dwelling dispute as to whether or not plant products produced by essential biological processes are patent-eligible 
The decision under appeal related to EP application EP2753168A1 assigned to Syngenta, and concerning pepper plants. Claim 1 recites a pepper plant characterized by specific quantitative trait loci as obtained by a conventional breeding method, but supported by the use of specific markers („smart breeding“). The application was rejected on 22 March 2018 under Art. 53 (b) EPC in conjunction with Rule 28 (2), on the grounds that the subject matter of claim 1 was excluded from patentability. 
Art. 53 (b) sets out that European patents shall not be granted to plant or animal varieties or essentially biological processes for the production of plants or animals. Rule 28 (2), which was introduced into the Implementing Regulations only in 2017, further clarifies that, under this article, European patents shall not be granted in respect of plants or animals exclusively obtained by means of an essentially biological process.
The amendment of Rule 28 was a response on a notice the European Commission issued in  November 2016 on certain articles of the “Biotech Directive”, in which the Commission took „the view that the EU legislator’s intention when adopting Directive 98/44/EC was to exclude from patentability products that are obtained by means of essentially biological processes.” (see this Gazette, Issue 6/2016). As we all know, the Commission’s view is not binding on anyone, and certainly not on the EPO, and the Commission does not have any jurisdictive powers either. 
It is only within the competence of the Court of Justice of the European Union (CJEU) to interpret EU law, and take binding decisions for the EU member states (which still would not be binding for the EPO, which is not a body of the European Union).
Nevertheless, shortly thereafter, the Administrative Council, overrode the Enlarged Boards of Appeal (EBA) decisions in "Tomato II" (G 2/12) and "Broccoli II" (G 2/13), according to which such claims were patent eligible, and implemented the Commission‘s findings into new Rule 28 (2) EPC. Before that, the President of the EPO had already ordered to stay all respective proceedings – a move which came (not so) surprising to many, as it, too, stood against decisions G 2/12 and G 2/13.
It seemed, at that time, that the President valued a non-binding opinion of a foreign executive higher than decisions of the highest jurisdictive body of the European Patent Convention – which was considered a slap in the face of the Boards of Appeal in general.
Back to the present case: Syngenta appealed the decision, arguing that Rule 28 (2) would be in conflict with Art. 53 (b). Since, under Art. 164 (2) EPC, the articles prevail the rules, Syngenta demanded that Rule 28 (2) must be declared inapplicable or otherwise interpreted. In the alternative, Syngenta requested to refer the case to the Enlarged Board of Appeal.
While in its provisional opinion, the Board had still declared that it would likely reject the appeal, it then decided otherwise, and declared Rule 28 (2) to be in conflict to Art. 53 (b), and hence inapplicable under Art. 164 (2). The Board then ruled that claim 1 is not subject of the patent exemption of Art. 53 (b), and remanded the case back to the examining division, to continue the examination for clarity and inventive step. 
The reasons for the decision have not yet been published, but will certainly be studied intensively. According to rumors, the Board did not see any need to refer to case to the Enlarged Board of Appeal, as its decision is in line with EBA’s precedent. 
The decision somehow reflects the deep disruption between the EPO’s executive, with the President as it’s spearhead, and the Boards of Appeal, and is the first one in history in which a Board of Appeal draws the nuclear option of Art. 164 (2). 
It will have to be seen whether this decision will endure, and how the executive bodies of the European Patent Office, as well as the European Commission, and primarily the examiners and opposition divisions, will deal with this decision.
Amgen’s blockbuster patent maintained in EP
Decisions strengthens functional antibody claims
07 December 2018 (3/2018) In issue 2/2018 of this Gazette, we discussed different aspects of the global dispute regarding Amgen‘s patents protecting their anti PCSK9 antibody Repatha. 
Therein, we also referred to Amgen’s European Patent EP2215124B1, which is opposed by 5 parties, among them Sanofi, Eli Lilly and Regeneron. 
Oral proceedings took place on November 29 and 30, 2018, and the outcome and some other aspects are now diffusing out, although the grounds for the decision have not yet been published. 
It seems that the Opposition Division remained true to itself, and maintained the patent in amended form, i.e., on the basis of a new main request that was already put on file in May 2017 – as already suggested in the Division’s preliminary opinion, which issued December 13, 2017.
Claim 1 as maintained is as follows: 
1. A monoclonal antibody or fragment thereof that binds to human PCSK9 and is neutralizing in that an excess of said antibody or fragment thereof is capable of reducing the quantity of PCSK9 bound to LDLR in an in vitro competitive binding assay, 
wherein said monoclonal antibody or fragment thereof competes for binding to PCSK9 with
(a) an antibody comprising a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEO ID NO: 23; or
(b) an antibody comprising a heavy chain variable region of the amino acid sequence in SEQ ID NO: 67; and a light chain variable region of the amino acid sequence in SEQ ID NO: 12.
Surprisingly, Claim 1 of the amended main request is hence identical to claim 1 as granted. Modifications Amgen effected applied only to other claims with less br9oad scope.  
Claim 1 is of the notorious „competes with“ style that is keeping the entire community upset, as the scope of such claim is extremely difficult to determine, and hence creates large uncertainties amongst competitors. 
We have discussed these claims in panel discussions at the BioConvention, May 2018 in Boston, as well as at the C5 Life Science Summit in Munich in October, with, inter alia, representatives of Eli Lilly and Sanofi, both of which have developed a very critical position regarding these claims. See also Issues 4/2016 and 2/2017 of this Gazette.
Unfortunately, these claims have so far not made to a Board of Appeal, at least to our knowledge. This may now change, because, not surprisingly, two of the opponents, namely Sanofi, and a strawman-lawfirm, have submitted appeals against the decision on the very same 2nd day of the oral hearing, directly after the Opposition Division declared its decision.
Hence, time will hopefully bring more clarity with regard to the patentability of these claims.
Federal Patent Court denies injunction for compulsory license
Praluent case decided differently than in the US
06 November 2018 (2/2018) In Issue 6/2016 of this Gazette we reported about the compulsory license the Federal Patent Court of Germany (BPatG) ordered in the Isentress case. In a nutshell, Merck & Co demanded a compulsory license for the sale of its anti-HIV drug raltegravir (Isentress), which yet fell under the scope of Shionogi’s European patent EP1422218B1,that protects dolutegravir (Ticay), to which Merck’s drug is structurally similar. 
At that time, the judges justified their decision with an urgent public interest to keep Insentress on the market, as it was authorized for some patient groups that were not covered by Shionogi’s drugs. They further acknowledged that Merck had earlier offered 10 mn USD for a global license. already available. 
The resulting compulsory license was the first one the court ordered in its 55-year history by way of a preliminary order. Quite understandably, the decision sent some shockwaves through the community. 
Recently, French drugmaker Sanofi tried as well. Its anti-cholesterol drug Praluent (the anti PCSK9 antibody Alirocumab) falls under the scope of European Patent EP2215124B1 assigned to Amgen, which protects, inter alia, Amgen’s competing antibody Evolocumab (Repatha).
The patent has the following independent claim:
1. A monoclonal antibody (..) that (...) competes for binding to PCSK9 with
(a) an antibody comprising a HCVR SEQ ID NO: 49; and a LCVR SEQ ID NO: 23; or
(b) an antibody comprising a HCVR SEQ ID NO: 67; and a LCVR SEQ ID NO: 12
Note that this claim is a so-called “competes with” claim, in which the claimed antibody is simply specified by its potency to compete for binding to a target with a reference antibody. 
This claim type is a subtype of the “epitope based claim”, type in which the antibody that is protected is not specified by structure, but merely indirectly, by the epitope it binds to on the respective target protein. 
These types of claims are subject to an ongoing controversy, as their scope encompasses a vast amount of antibodies, including antibodies that the patent owner has never made himself. 
Sanofi and Amgen are involved in a legal dispute in the United States related to corresponding US patents US8829165, US8859741, and others, all of which have as well epitope based claims (yet not of the even more controversial “competes with” type), and therefore encompass also Sanofi’s drug:
1. An isolated monoclonal antibody, wherein, when bound to PCSK9 (...)  binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369,S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and (..) blocks binding of PCSK9 to LDLR.
1. An isolated monoclonal antibody that (...) binds an epitope on PCSK9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and (...) blocks binding of PCSK9 to LDLR.
While in the first instance, the District Court declared the patent valid and issued an injunction against Sanofi, estopping them from marketing Praluent, the Court of Appeals of the Federal Circuit (CAFC) first overturned the injunction on grounds of public interest, and then remanded the case back to the District Court, to re-examine the validity of the patent. In its decision, the CAFC ordered the District Court to reconsider if the genus claim (= the epitope claim) is supported by representative species (= sufficient examples of structurally defined antibodies that bind the epitope). It remains however unclear what a sufficiently large number of species is. 
While the District Court’s decision is still pending, the USPTO has already instructed its examiners no longer consider a newly characterized epitope as adequate written description for an antibody claim.
Meanwhile, Amgen has filed a petition for certiorari to the Supreme Court, alleging that the CAFC’s ruling would result in “jurisprudential anarchy”. Amgen claims that the patent act would require that a patent specification simply teaches others to make and use the invention, instead of demanding possession of invention. In fact, with this submission, Amgen is challenging that Written Description is a distinct requirement separate from the Enablement Requirement (as established in Ariad vs Lilly). 
Epitope based claims in general, and this case in particular, are/is probably one of the most discussed topics among Bioech IP professionals these days. We have discussed these claims in panel discussisons at the BioConvention, May 2018 in Boston, as well as at the C5 Life Science Summit in Munich in October. Please request the slides here. See also Issues 4/2016 and 2/2017 of this Gazette.
Back to the German case. Sanofi had filed an action at the Federal Patent Court under § 24 and § 81 of the German Patent Act, to order a compulsory license under reasonable royalties. Further, Sanofi demanded a preliminary order under § 85.
§ 24 sets forth that a compulsory licensee may be awarded to a petitioner if the latter has unsuccessfully tried to obtain, within a reasonable period of time, a license from a patent proprietor, while the public interest demands such license.
§ 85 provides that compulsory licenses can be awarded by means of a preliminary order, provided that such license serves public interest.
The Court denied Sanofi’s request. First, the Court found that Sanofi had not made sufficient efforts to obtain a license on reasonable commercial terms. Sanofi had made a short offer to Amgen on June 20, 2018, however, only three weeks later, on July 12, 2018, they filed the request for a preliminary order with the Court.
The Court also found that Sanofi should have started their attempts to obtain a license earlier, in particular because the corresponding infringement proceedings were resumed in December 2017 already, and because the study Sanofi referred to in order to demonstrate the public’s interest in a compulsory license (which study showed that Praluent would reduce total mortality in high risk patients by 29%, compared to a Placebo) was available in March 2018 already. 
Hence, the Court concluded that Sanofi’s letter of 20 June 2018 would constitute a "last-minute offer", and would not fulfill the condition of “within a reasonable period of time”, as set forth in § 24.
Second, the Court found that Sanofi did not sufficiently demonstrate that there was a public interest in the further free availability of Praluent, as they had failed to make convincing arguments that other products on the market - in this case, Amgen’s Repatha, did not possess the (particular) therapeutic properties of Praluent in equal measure. 
Note that this decision only referred to Sanofi’s request for a preliminary order to award a compulsory license. However, the final determination of the merits of the case (3 Li 1/18) is still pending.
Notably, European Patent EP2215124B1 is opposed by 5 parties, among them Sanofi, Eli Lilly and Regeneron. Oral proceedings will take place at the end of November 2018. 
The outcome of this case will be quite interesting, because here claims of the highly controversial “competes with” type will be at stake. The last major opposition case in which this claim type was at issue was the Opposition against BMS’s patent EP2161336B1 (see this Gazette, issue 3/2017). 
However, in that case, BMS cancelled the respective claim 3 in the course of the proceedings, so the Opposition Division did not have to decide upon it.
It will also be interesting to see whether the recent developments in the United States, raising the bar to such type of claims, have an influence on the Opposition Division’s decision. 
The Division’s preliminary opinion, however, which issued December 13, 2017, suggests that the patent will likely be maintained in unamended form. 


Waxman against Hatch in Hatch Waxman -
Former coauthors of generics US legislative pathway in confrontation mode
06 November 2018 (2/2018) The legislative proposal by one of the architects of the Hatch-Waxman Act to effectively bar generic drug makers from challenging patents at the US Patent Trial and Appeal Board has not found consent of the bill's other named sponsor.
The Drug Price Competition and Patent Term Restoration Act, also known as "Hatch-Waxman Act" referring to its initiators and authors, Senators Orrin Hatch and Henry Waxman, was enacted in 1984 to establish a legal system for generic drug regulation in the US as amend-ment of the Federal Food, Drug and Cosmetic Act. The new Section 505(j) of the latter (co-dified as 21 U.S.C. 355(j)) out-lines the process of filing an ab-breviated new drug application (ANDA) for approval of a generic drug by the FDA, and was intended to provide some protection for drug innovators on one hand but also incentives for facilitated filing of ANDAs by generics manufacturers on the other hand.
In drug innovators‘ favor, the Hatch-Waxman Act introduced a new five-year data exclusivity period upon market approval of a new chemical entity, during which period the FDA cannot approve a generic version of the drug. In addition, the institute of patent term extension (PTE) was established to account for time the patented product is in clinical phase testing and under review by the FDA.
The generics industry gained the ability to obtain approval through ANDAs based on manu-facturing information and bio-equivalence studies, the ability to challenge brand drug patents prior to marketing in court while enjoying safe harbor from infringement lawsuits during ANDA preparation, and gained 180-day generic drug exclusivity for the first runner in the field receiving ANDA approval.
As key concepts of the Hatch-Waxman Act which significantly promoted introduction of generic drugs – from only 13% of total prescriptions in 1983 to 84% in 2012 – the innovator has to have relevant patents listed in the Orange Book and the generics company has to certify with respect to each patent in the list; upon "paragraph IV certifi-cation“ claiming that a patent is invalid or not infringed by the ANDA product, the innovator is prompted to commence patent litigation against the generics entity who in turn can file countersuit to have respective Orange Book patents declared invalid.
In order to strike similar balance between innovation and afford-ability for biologic drugs, in 2009 the Biologics Price Competition and Innovation Act (BPCIA) provided incentives for biologic innovators and created abbre-viated pathway for biosimilar makers.
In addition to said court litigation however, Inter-Partes Reviews at the Patent Trial and Appeal Board (PTAB) of the USPTO, created by the America-Invents-Act in 2012, have become an in-creasingly important institute over the last years to challenge and invalidate drug innovator patents independently of the litigation pathway tied to the regulatory approval process.
Last June, Senator Hatch pro-posed an amendment[1] entitled the "Hatch-Waxman Integrity Act of 2018" with the purpose to "ensure that Hatch-Waxman continues to operate as original-ly intended by protecting the ability of generic drug com-panies to develop low-cost drugs while at the same time ensuring brand-name companies have sufficient protection in place to recoup their investments". Allegedly, generic and biosimilar manufacturers were increasingly utilizing IPR proceedings for patent invalidation while circumventing the HWA and BPCIA regimes, leading to added litigation pressure on innovator companies and giving generic companies who lost in Hatch Waxman litigation a second chance to challenge a drug patent ("getting a second bite at the apple").
Hatch’s proposal aims to "close the loophole unintentionally created" by the AIA and "restore the careful balance" of the HWA and the BPCIA. According to the proposal, generics/biosimilar makers wishing to challenge a brand drug or biologics patent, and related entities ("any party in privity with the applicant"), will be required to (i) choose between the specific HWA/BPCIA patent procedures and the Inter Partes or Post-Grant Review proceed-ings under the AIA, rather than taking advantage of both; and (ii) not rely "in whole or in part on any decision issued by" the PTAB as evidence that the brand patent is invalid in the HWA or BPCIA procedures.
Said amendments to be made to Section 505 of the Federal Food, Drug and Cosmetic Act for chemical compounds and to Section 351(k) of the Public Health Service Act for biosimilar compounds would intend "to prevent the Inter Partes Review process for challenging patents from diminishing competition in the pharmaceutical industry and with respect to drug innovation".
The proposal is being heavily discussed and – of course – highly controversial. Enactment of the amendment would require an ANDA or biosimilar applicant to choose between engaging in the ANDA/biosimilar approval pathway or challenging a patent in an IPR or PGR proceeding. The latter have been perceived as faster and cheaper alterna-tives to long and costly counter-suits. However choosing that route apparently would mean that the applicant would not any more be able to rely on the brand company’s safety and efficacy studies for FDA approval, with drastic consequences for budget and time-lines. In Hatch’s own words:
"The party can file a Hatch-Waxman suit, which carries the benefits of being able to rely on the brand company’s safety and efficacy studies for FDA appro-val, or file an IPR proceeding, which is cheaper and faster, and easier to win. But it can’t do both“. [1]
Last week now, Senator Henry Waxman announced that he will be "vigorously opposing" the idea of Hatch’s amendment. Drug regulatory experts and IP specialists alike are keen to see how this concept will play out in view of these opposing stand-points and the fact that Senator Hatch is expected to retire in January 2019.
[1] “Hatch Amendment to Incentive Generic Drug Development”, Senator Hatch Press Release, (June 14, 2018) 
European Sovaldi patent stands attack by NGOs
Patent maintained in amended form, but Gilead says: still string enough
28 September 2018 (1/2018) Gilead’s Sovaldi (Sofosbuvir) is a nucleotide analogue that is being used for the treatment of Hepatitis C, in a combination with other drugs.
It is generally considered to be a breakthrough therapy, and a true gamechanger in the treatment of HCV – a disease with otherwise may lead to liver cancer, and often a painful death after years of suffering. 
Hence, a blessing for humankind, one would think, if there weren’t the price tag. Sovaldi made its way through the media as the „1000 Dollar“ pill. 
Treatment costs for a 12 week therapy in the United States were reported to be up to 84,000 USD, while in India Gilead sells the drug for 300 USD per therapy, and has granted licenses to leading Indian generic companies. Still, Gilead’s pricing policy in the industrialized markets has been subject to much criticism.
This seems to be one of the reasons why Doctors of the World, Doctors without Borders, and the European Public Health Alliance (EPHA), filed an opposition against Gilead’s EP patent EP2604620.
Oral proceedings took place on Sept 11, 2018, and, as a consequence, the patent was maintained in amended form. The decision is not yet publicly available, but we will keep you tuned. 
The three NGOs joined forces and submitted identical opposition briefs, which comprised the admissible grounds for revocation (lack of novelty and inventive step, added matter, insufficient disclosure), but also an introductory section where Gilead’s drug pricing policy was denounced.
Without knowing the exact outcome, it appears that the attacks were not strong enough. Or, in other words: Drug pricing is not a ground for opposition at the EPO.
However, Gileads IP position on Sovaldi is under higher pressure in other jurisdictions. The corresponding patents in Brazil and China were recently revoked. And on March 14, 2018, the NGO Knowledge Ecology International (KEI) launched an initiative against Gilead, by demanding the Department of Health and Human Services (HHS) to investigate a potential failure to report NIH funding for research that lead to Gilead’s Sovaldi patent US7964580. Such failure would violate regulations set forth in the Bayh Dole act, and hence force Gilead to forfeit its title to the patents. 
And, Sovaldi is not the only patent front Gilead is fighting at. On May 15, 2018 the Federal Patent Court of Germany (BPatG) declared the supplementary protection certificate (SPC) DE122005000041 for Gilead’s combination drug Truvada, (tenofovirdisoproxil and emtricitabine), which is an anti HIV treatment, invalid, hence opening the market for generic versions thereof. 
The SPC was declared invalid because, while emtricitabine is also protected by the basic patent, the combination isn’t. The Court argued that an SPC may only include what is also protected in the basic patent.
In this decision, one of the many unclarities of the EU’s SPC regulation comes again into focus, with the Court of Justice of the European Union (CJEU) having proven unable to clarify matters despite the fact that it has already issued more than a handful of decisions addressing this question (see issue 5/2013 of this Gazette). 
The BPatG decision is not yet published. Yet on July 5, 2018 the CJEU decided a referral by a UK court, which related to the corresponding UK SPC. Like the German counterpart, the latter was based on EP patent EP0915894. The CJEU revoked the SPC for the same reasons as the BPatG. This decision can’t be appealed and will also have a bearing on a potential appeal in Germany.
P.S. Gilead’s Truvada SPC in Switzerland has been declared valid in June 2018. Do I here someone complaining about lack of harmonization? Well, you are right. Welcome to our world. We call it Europe.
Broad prevails in CRISPR Cas9 interference
CAFC: Broad’s patent claims separately patentable from the claims of UC Berkeley’s patent application.
28 September 2018 (1/2018) On September 10, 2018, the Court of Appeals of the Federal Circuit (CAFC) issued a long awaited decision, and confirmed a decision of the Patent Trial and Appeal Board (PTAB) of 2017, in which the latter denied that Broad’s patent portfolio covering CRISPR Cas9 technologies would interfere with UC Berkeley’s earlier patent portfolio, covering similar subject matter (see issue 1/2017 of this Gazette).
In a nutshell, UC Berkeley, with inventors Jennifer Doudna and Emanuelle Charpentier, established a simplified way to use the bacterial system CRISPR Cas9 as a genome editing tool, though they could demonstrate the use of this tool only in prokaryotes. Broad Institute, with Inventor Feng Zhang, claims to have invented a way to use the tool in eukaryotes, too. 
The CAFC now confirmed that the claims of Broad’s patents are sufficiently distinct as to be separately patentable from the claims of the Doudna/Charpentier group’s patent application.
We have discussed the underlying patent dispute in two articles (Les Nouvelles (2018), 123 – 131 and J Biotech 265 (2018), 86-92). Please write us here for copies.
UC Berkeley used its then pending application US20140068797 as a basis for the interference. However, examination thereof was stayed when the interference began, so the final scope of this application remains unclear until to date. 
When the application went into hibernation, the then pending set of claims was however not restricted to neither prokaryotes nor eukaryotes – the major restriction then was the chimeric sgRNA which is generally accepted to be Doudna’s and Charpentier’s invention.
Now, with the interference proceedings terminated, the examination of US20140068797 can be resumed. 
In the meantime, UC Berkeley has filed a divisional application (14/685,502), which was granted on June 19, 2018 as US10000772. 
The independent claim of this patent relates to a method of modifying a target DNA molecule using Cas9, but is restricted to 
„contacting the target DNA with the CRISPR Cas9 complex outside of a bacterial cell and outside of an archaeal cell“
So what does this mean? The language is actually quite ambiguous as, strictly speaking, it excludes in vivo use in bacteria and archea, meaning it could encompass in vitro and in vivo use in eukaryotes. 
Such claim construction would however directly interfere with Broad’s patents portfolio (US8697359 et al.) that was subject of the interference, and would collide wíth the CAFC’s finding that Broad’s patents which specify that the CRISPR-Cas9 system is used in eukaryotic cells would be separately patentable from Broad’s patent claims
In other words: In view of the new decision, UC Berkeley’s patent could prove unenforceable. The problem seems to be written description, which UC Berkeley actually has not provided for the use of the new technology in eukaryotes. These more sophisticated organisms require that the enzyme is shuttled into the nucleus – for which purpose Broad used so-called NLS sequences, which are lacking in the UC Berkeley applications.
However, what looks like only a prelude to a whole series of further lawsuits could also be a trigger for settlement. 
This is because UC Berkeley has recently obtained a double success in Europe, with their key patent EP2800811 being granted (although already under opposition) with relatively broad scope (note Europe does not have a written description requirement), and the first of Broad’s patents being revoked in 1st instance opposition, due to a priority problem – which It shares with its other EP members from the same family.
Hence, both parties have had their successes and their losses – sounds like a good starting point for a settlement, doesn’t it? If there weren’t the other players, and the exclusive licenses that have already been granted.

AbbVie and Amgen agree to put Amjevita into the waiting room


Humira one step closer to exclusivity until 2022


6 October 2017 (8/2017) AbbVie’s Humira patent strategy is a model case about how to fend off a blockbuster from generic competition.


We have previously reported about the Humira patent estate. Find our article “Of patents and patent disputes: The TNFα patent files” here, or ask for a reprint.

In the past, AbbVie’s CEO, Richard Gonzalez, made several full-bodied announcement that due to the extensive patent strategy, Humira would be protected from biosimilar competition until 2022, and, based on this strategy, AbbVie’s sales would climb to 18 bn USD by 2020.


Now it seems that, due to a recent agreement with Amgen, Mr Gonzalez is one step closer to keeping this promise.


Despite an ongoing patent litigation between the two parties, the FDA has on September 23, 2016 approved Amgen’s adalimumab biosimilar AmjevitaTM (“adalimumab-atto”). Approval in Europe (where the product is called Amgevita) followed March 23, 2017.


The biosimilar comes in a 40 mg/0.8 ml or 20 mg/0.4 ml prefilled syringe or prefilled autoinjection pen. The formulation of Amjevita differs markedly from that of Humira, in particular in that it comprises an acetate buffer instead of the citrate/phosphate buffer, and sucrose instead of mannitol – a difference which obviously did not affect its biosimilar status. Amjevita is approved for the commercially most important indications of Humira. Yet, Amjevita still did not make it to the US market so far, and now we know why.


On Sept. 28, 2017, Amgen surprisingly announced that they have reached a settlement with AbbVie.

Under this settlement, the parties have agreed that Amgen will wait until Jan. 31, 2023, to launch Amjevita, in the U.S, while in Europe market entry is expected sooner, namely Oct. 16, 2018.

Reportedly, the settlement includes a patent license awarded to Amgen and royalties Amgen has to pay.

Yet the agreement seems to be a setback for Amgen, because in 2016, Amgen indicated that due to the ongoing litigation with AbbVie, it would be unlikely that Amjevita would see US market launch before 2018 – while, initially, 2017 was the year they had in the focus. So the delay of market entry now adds up to about 5 years.

Still, in their press release regarding the settlement, Amgen announced that the agreement would allow them to secure a strong foothold in the $4 billion European adalimumab market.

With the caveat that Amgen is not alone there.

Due to a weaker patent position in Europe (see several issues of this Gazette), quite a few players have already staked their claims on European ground.

On August 24, 2017, the European Commission granted marketing authorization for Samsung Bioepis’ Imraldi.

Boehringer Ingelheim’s BI 695501 (now called Cyltezo) was accepted for regulatory review by the European Medicines Agency in January 2017, and received a positive opinion in September 2017, making an approval likely in the fourth quarter of 2017.

And, on May 18, 2017, the EMA has accepted Fuji Kirin’s FKB327 for review.

Hence, the adalimumab biosimilar market in Europe is going to be quite competitive.



Double win for Kymriah CAR-T


First Car T cell product approved, and also patented


6 October 2017 (8/2017) On August 30, 2017, the US Food and Drug Administration (FDA) approved Novartis new CAR-T cell therapy KymriahTM (tisagenlecleucel),  formerly called CTL019. Kymriah is the first approved chimeric antigen receptor T cell (CAR-T) therapy, and is approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) which are refractory or in second or later relapse.


Kymriah is a one-time treatment consisting of T-cells taken from the patient, engineered to comprise a Chimeric Antigen Receptor (CAR), and re-administered to the patient.


The CAR essentially consists of an anti CD19 scFv (commonly known as FMC63) a transmembrane domain, 4-1BB as costimulatory domain and a CD3ζ signaling domain.


The thus programmed T-cells do then effectively attack and eradicate lymphoblastic cells that featured CD19 on their surfaces, with so far unprecedented efficacy.


The success came quite surprising after one of Novartis’ competitors, Juno Therapeutics, discontinued its lead CAR-T cell candidate JCAR015, probably because five people died in a trial.


JCAR015 has a similar structure as Kymriah, yet a different anti CD19 scFv (known as SJ25C1), and CD28 instead of 4-1BB as a costimulatory domain


Novartis reports in a press release that that an 83% (52/63) overall remission rate was obtained in a patient chohort comprising children and young adults with B-cell ALL that is refractory or has relapsed at least twice.

Said new therapy comes with a price tag. $475,000 is what Novartis demands for a treatment. Admittedly, Kymriah  seems to be very efficacious. Patients usually need it only once, and the R&D costs until approval must have been horrendous. 


Hence, Kymriah seems to be an asset that actually justifies sound patent protection.


And, Novartis and its licensor, University of Pennsylvania (UPenn) have done their homework. On July 19, 2017, European Patent was granted to UPenn, with, inter alia, the following claim 1:


1. A T cell genetically modified to express a CAR wherein the CAR comprises


(a) an antigen binding domain that is an anti-CD19 scFv comprising the amino acid sequence of SEQ ID NO:20,

(b) a costimulatory 4-1BB signaling region, and

(c) a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO: 24,


for use in a method for treating cancer in a human, wherein a remission of the cancer is obtained, and wherein the human is resistant to at least one chemotherapeutic agent.


Now it appears that the scope of this patent is so broad that it also encompasses two other of Juno’s candidates, JCAR014 and JCAR017, which both have FMC63 as anti CD 19 scFV), 4-1BB as costimulatory domain and a CD3ζ signaling domain.


Although the sequences that Juno uses in these two candidates are not disclosed, it appears at least likely that the two candidates fall under the scope of UPenn's patent.


And, Juno is not the only competitor. Servier’s UCART19 also targets CD19 (although unclear which antibody is used) and uses 4-1BB as a costimulatory domain


What is also interesting is that UPenn’s patent was granted despite the fact that a CAR T cell comprising a CD19/4 1BB/CD3ζ receptor construct has already been disclosed in prepublished US patent 7,446,190 (assigned to Sloan Kettering and licensed by Juno Therapeutcs).


The EP examiner was aware of this prior art reference, yet, obviously, a later added restriction according to which a remission of the cancer is obtained, and the patient is resistant to at least one chemotherapeutic agent was deemed sufficient to render the claims non obvious.


Another prior art document is US patent 8,399,645 (assigned to St Jude’s hospital, and likewise assigned to Juno), which also discloses a CAR T cell with the said three elements.


The opposition term of the patent ends April 19, 2018. With similar price tags for competing products in mind, it appears that competitors developing CAR-T cells with a CD19/4 1BB/CD3ζ receptor construct will have enough motivation to file oppositions. We will keep you tuned.




CAFC calls epitope based antibody patents in question

But, swan song on epitope based claims not yet sung


6. October 2017 (7/2017)  In Issue 4/2016 of this Gazette, we reported about a district court decision in which Amgen had received a 1st instance win against Sanofi at and Regeneron (1:14-cv-01317). The dispute circled around Sanofi’s and Amgen’s anti PCSK9 antibodies, which bind to the receptor for low-density lipoprotein (LDL) that are used in the treatment of hyperlipidemia.


The two antibodies, alirocumab (Praluent®, Sanofi) and evolocumab (Repatha®, Amgen) received FDA approval in 2015 for lowering cholesterol where statins and other drugs were insufficient.


The patents Amgen relied upon are US8829165, claim 1 of which is as follows


1. An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.


and US8859741, claim 1 of which is as follows:


1. An isolated monoclonal antibody that binds to PCSK9, wherein the isolated monoclonal antibody binds an epitope on PCSK9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.


The court found (i) that Sanofi’s Praluent would fall under the scope of these claims and (ii) that the claims are valid. As a consequence, the court granted an injunction against Sanofi, forcing the latter to withdraw Praluent from the market.


The injunction, in particular, sent shockwaves through the pharma community, because there had already been patients who had a prescription for Praluent, and who would have been deprived them of their actual heart medication.


We discussed this decision as the “return of the epitope-based antibody claims”. This claim species is often used  as a fallback position for antibody protection in case the target as such is already prior art, because it provides broader protection scope of protection then antibody claims protecting the mere antibody sequence.


For this reason, epitope-based antibody claims are still quite popular among antibody companies. See e.g. U.S. patent 8,779,105 assigned to Ono and licensed by BMS, which claims “a monoclonal antibody or an antigen-binding portion thereof, which cross-competes for binding to PD-1 with a reference antibody” specified by a given sequence (we discuss this patent in an article that can be found here).


Not surprisingly, however, Sanofi went into appeal to the CAFC. In the respective suit, both sides were aided by amicus curiae briefs from different parties, including Eli Lilly (to support Sanofi’s position) and AbbVie (to support Amgen’s position).


On February 8, 2017, the CAFC decided to stay the injunction for the duration of the appeal proceedings, hence allowing Praluent to remain on the market. While this was considered to be a stage win for Sanofi, the question whether or not the Amgen’s claims were valid was still pending.


Until yesterday, Oct 5, 2017, to be precise, when the CAFC issued its decision to remand the case back to the first instance.


The decision vacated the permanent injunction and ordered that Sanofi’s lack of written description and lack of enablement defenses are to be reconsidered. In the eyes of the CAFC, the District Court had erred by categorically excluding evidence regarding those defenses. The CAFC emphasized that the District Court must allow the jury to consider Sanofi’s post-filing evidence in determining whether Amgen’s patent specification discloses a “representative number of species” sufficient to show possession of the claimed genus of PCSK9 antibodies binding a particular epitope.


Ok, what do we learn from this ?


Considering that the case is not yet finally decided, epitope based claims can be valid in case the applicant provides a sufficient number of antibodies that bind to the respective epitope – probably to different subsections thereof, and probably combined with a non-working example of an antibody that binds outside of that epitope – to demonstrate true intellectual possession  of the claimed epitope


In case the applicant has just one candidate antibody, and claims all antibodies that compete with that respective reference antibody for binding to the target (as it has been done in Ono’s anti PD-1 antibody patent discussed above), said written description will hardly be fulfilled.




CRISPR patent dispute makes it to down under


6. October 2017 (7/2017) As we discussed in Issue 6/2017 of this Gazette, Sigma Aldrich has recently received grants for an Australian patent (AU2013355214B2), and a European patent (EP3138910 B1).


The scope of the two patents is essentially identical, covering the integration of a donor/exogenous sequence into a chromosomal sequence of a eukaryotic cell by an RNA-guided endonuclease comprising at least one nuclear localization signal.


Interestingly, the EP patent is restricted to CRISPR/Cas type II systems, while the AU patent isn’t.


In the EP patent, the opposition term will end June 20, 2018. In the AU patent, the opposition term has already ended Sept 15, 2017.


Not entirely surprisingly, three strawmen have filed oppositions against the Australian patent.


Hence, the CRISPR patent dispute has now eventually made it to down under.



Yet another CRISPR player

Headcount is now five


28 August 2017 (6/2017) Quote 1 of the last Gazette: “The CRISPR Cas IP dispute has often made it into this Gazette”. Quote 2 of the last Gazette: “3rd and 4th player on stage”


Well, today we can report about a fifth player who owns patents protecting the CRISPR basis, Sigma Aldrich, who remained under the radar of most or a long time.


Sigma Aldrich has recently received grant for an Australian patent (AU2013355214B1, and is about to get a European patent grated EP3138910A1).


As regards the priority date (Dec 6, 2012), Sigma Aldrich ranks fourth after Vilnius University (March 20, 2012), UCBerkeley/Vienna University (May 25, 2012) and Toolgen (Oct 23, 2012), but before Broad Institute, who however received granted patents first, due to expedited prosecution both in Europe and the United States.


What makes the Sigma Aldrich’s portfolio so relevant is that it discloses and enables the use of CRISPR Cas 9 in eukaryotes, by means of a Nuclear Localization Sequence (NLS) already in the priority document.


This is what Broad Institute has always claimed to be its discriminating feature over the UC Berkeley portfolio, in which such transfer from prokaryotes into eukaryotes was not yet disclosed or enabled at the priority date. 


Actually, such transfer and use of NLS is also disclosed and enabled in the Toolgen portfolio’s priority application, which however has not yet received grant, with the exception of Korea (KR101706085B1).


Hence, the recent development regarding Sigma Aldrich’s portfolio could make an already complicated IP situation even more complicated.



AbbVie gives up Humira’s European formulation patents


Still, Humira not yet open to generic competition in Europe


28 August 2017 (6/2017) In an article that issued in 2017, we have discussed the patent strategy underlying the world's best selling drug, AbbVie's Humira. Please send an email if you want a copy.


One of the key families is the so-called Krause family, which protects Humira’s established and approved formulation, comprising 40 mg/0.8 ml (hence 50 mg/ml) in a citrate/phosphate combination buffer.


The respective EP patent EP1528933B1 was revoked in 1st instance opposition proceedings on Oct 13, 2015 for lack of novelty. In fact, AbbVie had committed a fatal flaw during prosecution. Upon filing the underlying priority application, AbbVie forgot to submit the light chain/heavy chain variable domain sequences to which the formulation claims referred. Shortly after the priority date, the actual formulation was published, but only after that, AbbVie submitted the sequences with the USPTO. In the European prosecution, this issue escaped the attention of the examining division, but in subsequent opposition proceedings, the priority date of the application was re-dated to the date when the sequences were submitted, with the result that the published formulation became novelty-destroying prior art against the patent claims.


In an attempt to re-establish the earlier priority date, AbbVie then tried to replace the sequence by the term “D2E7”. This attempt was found unallowable by the Opposition Division because of lack of clarity of that term, which furthermore was found to extend the scope of the claims post grant, and hence unallowable.


Not surprisingly, AbbVie appealed the decision, and, actually quite surprisingly, submitted an excerpt from the CAS registry database (entry No 331731-18-1) which discloses the full length heavy/light chain sequences of adalimumab, which was allegedly available to the public since April 18, 2001. This allegation was vigorously disputed by the opponents, who objected that said entry identified the chemical name “D 2E7” with a blank space between “D” and “2”, whereas a search for “D2E7” (without blank space) did not deliver this register entry.


It almost appeared that AbbVie may have actually tried to conceal the full length sequence of adalimumab in said register simply by annotating it with a misspelled chemical name.


Further, AbbVie has recently received grant for a further divisional application (EP2359856B1) with amended claims that faithfully reflect the approved formulation in all details, with the exception that, again, the term “D2E7” is used. Here, the same clarity issues applies, less the issue regarding post-grant extension of scope, because the application was still pre-grant when the term D2E7 was introduced into claims.


Much to our surprise, Abbvie has last Monday (Aug 21, 2017) proactively revoked European patent EP2359856B1, still within the opposition term. On the same day, AbbVie has also withdrawn its appeal against the revocation of the parent patent, EP1528933B1.


Further divisional applications in the family (EP2361637, EP2363144 and EP2363145) are all finally withdrawn since 2016. This means that AbbVie has completely given up the European IP portfolio that protects its citrate phosphate buffer.


Humira as such is off-patent in the United States already. US patent US6090382 expired Feb 9, 2016, plus a PTE extension until Dec 31, 2016. However, its European counterpart, EP0929578B1 is still in force until Oct 15 or 16, 2018, due to a supplementary protection certificate plus pediatric extension.


Therefore, despite that step, Humira is not yet exposed to generic competition in Europe.


Still, the rationale behind AbbVie’s tactics still remains enigmatic for us. According to US Philosopher Eugene T Gendlin, a key feature of guerilla warfare is to “borrow the enemy's resources, and to conquer and withdraw immediately”. Now you would not actually qualify AbbVie as a guerilla – but we can’t help to see similarities, tactics-wise.