Tag Archives: CAFC

SCHRÖDINGER’S POLYMORPH: WHEN A CRYSTALLINE FORM CLAIM IS OBVIOUS AND INVALID

Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024)

“Schrödinger’s cat,” is a paradoxical thought experiment devised by physicist Erwin Schrödinger, while debating quantum superposition in 1935. Oversimplified, in the thought experiment, there is a cat in a box, and you have no way of knowing what physical state the cat is in, like a quantum wave function, until you open the box and observe it.

While studying polymorphic forms, like Schrödinger’s hypothetical [albeit a long stretch], you do not know what form a solid compound is until you measure it with x-ray crystallography. However, unlike Schrödinger’s hypothetical, you may have a reasonable expectation of succeeding to figure out what form your compound is depending on the prior art and knowledge of a person of ordinary skill.

Shifting from quantum to organic chemistry patent law, if there is a reasonable expectation of success in characterizing a known crystalline product for potential polymorphism using routine, conventional methods and skill, then a claim to that crystalline product would be invalid for obviousness. Such was the decision in Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024).

Salix claimed a specific crystalline form (form β) of rifaximin. The United States patent and Trademark Office (USPTO) granted Salix a patent on it.  However, when litigated, the United States Court of Appeals for the Federal Circuit (CAFC) affirmed the District Court of Delaware’s finding that Salix’s claims to rifaximin form β were invalid for obviousness.*

“The difference between the prior art and the claims is thus effectively nothing more than the performance of routine characterization to identify the polymorphic forms that result from the known Cannata processes.”

Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024), at 15.

In other words, you cannot claim ownership of a compound just by making the expected crystalline form using someone else’s process and taking an x-ray crystal structure of it and giving a Greek letter name.

Background

  • Salix markets Xifaxan® (rifaximin), and Norwich wanted to sell a generic version.
  • Xifaxan® is a formulation of rifaximin crystalline form β.
    • Polymorph β is a commonly produced polymorph.
    • Polymorph β the most stable form of rifaximin.
  • Disputed patent claims: Claim 4 of U.S. Patent No. 7,612,199 and Claim 36 of U.S. Patent No. 7,902,206.
    • Claim 4. Rifaximin in polymorphic form β, wherein the rifaximin has x-ray powder diffraction pattern peaks at about 5.4°; 9.0°; and 20.9°2θ and wherein the rifaximin has a water content of greater than 5%.
  • Prior art: Cannata et al. U.S. Patent No. 4,557,866.
    • Although Cannata does not discuss rifaximin’s crystal structure in detail, it does disclose several preparation protocols for rifaximin that include solvents used for crystallization.
    • Experts testified that Cannata’s preparation of crystalline Rifaximin would have yielded its β form. But they could not say it would every time.
  • Rifaximin was a known compound with a known, useful activity (antibiotic).
    • While rifaximin was a known antibiotic, Salix owns rights to patents covering new method of use (hepatic encephalopathy). Salix won on appeal for such method-of-use claims.
  • Experts testified that Cannata’s preparation of crystalline rifaximin would have easily made and taken an X-Ray diffraction pattern to determine that rifaximin was in its β form.
    • The experts could not convince the judge that the prior art process would produce rifaximin form β “every time.” If they could, then Salix’s claims would have been anticipated (not novel) as inherently present in the prior art.‡
    • Although the experts could not convince the judge of the certainty of form β (novelty), they at least convinced the judge that form β was reasonably expected (obviousness).

    CAFC Opinion Discussion

    The CAFC decided that “the district court found a reasonable expectation of success in characterizing the crystalline product of Cannata for potential polymorphism using routine, conventional methods and skill [Salix Pharm., Ltd. v. Norwich Pharm., Inc., Civil Action No. 20-cv-430-RGA, (D. Del. Apr. 29, 2021), at *6–7].†  We see no clear error in that conclusion. Indeed, Salix has done no more than combine known elements of the prior art to verify readily accessible information concerning a compound already in the hands of those of ordinary skill in the art, and such routine efforts do not justify removing this polymorph from the public domain. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007); see also Pfizer, 480 F.3d at 1367−68.”

    The District Court supported its factual determinations of obviousness with expert testimony that:

    (1)  a skilled artisan would have had good reason to characterize the crystalline rifaximin obtained by following the Cannata protocols,

    (2)  such characterization was routine and could have been performed “in one day,” and

    (3)  doing so would have led the skilled artisan to have “detected rifaximin β.” 

    Salix argued that a person of ordinary skill in the art would not have “expect[ed] to succeed” because, as of the critical date, the polymorphic nature of rifaximin had not yet been reported and the identity of the β form remained undisclosed. They further argue that a skilled artisan would not have been able to predict which polymorphic form Cannata made. This argument was flawed. The CAFC states that Salix’s is incorrect in framing of the issue, as it suggests that no unknown entity could ever be obvious, as one cannot reasonably expect what was hitherto unknown.

    * In the same appeal, The CAFC did affirm the District Court’s finding that Salix’s other claims to methods of treating hepatic encephalopathy were valid and nonobvious.

    † Whether or not there would have been a reasonable expectation of success is a question of fact. “Whether or not there would have been a reasonable expectation of success is a question of fact, (IXI IP, LLC v. Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed. Cir. 2018)), which we review for clear error, Hospira, 946 F.3d at 1328. We review the ultimate conclusion of obviousness de novo.” Did the Justices themselves believe that the claims were obvious? Unknown. The CAFC perhaps equivocated or sidestepped the question. The justices did not say that they themselves believe that the polymorph claims were obvious. Rather, they merely said that they found no clear error in the District Court’s finding of obviousness. 

    ‡ The CAFC did not opine on whether or not the polymorph claims were invalid for being inherently anticipated (§102). The court said that they did not need to go that far since they already determined that the claims were invalid for obviousness (§103). The district court said that the polymorph claims were not anticipated as being inherent because Norwich did not prove with clear and convincing evidence that the prior art method would produce rifaximin form β “every time.” The inherency issue may deserve its own post. Question for discussion: Does the “every time” requirement go too high for “clear and “convincing evidence?” Perhaps requiring a specific result Every time may go up to the realm of “beyond a reasonable doubt,” which is not the level of burden of proof for patent law. Recall last year’s discussion of the Amgen case where there were arguments about how many examples enable the “full scope” of a claim. Stay tuned.

    Additional Information

    OrganicPatents.com page on Obviousness of Stereoisomers &Purified Compounds

    Obviousness of Stereoisomers & Purified Compounds

    See also PatentDocs’s post: https://www.jdsupra.com/legalnews/salix-pharmaceuticals-ltd-v-norwich-3362384/.


    May 8, 2024

    Inherency & Therapeutic Mechanisms: Reviewing In re Couvaras – (With No-Frills Diagrams)

    Q:  When can you patent a composition’s mechanism of action?

    A:  When the mechanism is not inherent in a known use of the composition.

    “Reciting the mechanism for known compounds to yield a known result cannot overcome a prima facie case of obviousness, even if the nature of that mechanism is unexpected.”

    In re Couvaras, 22-1489 (Fed. Cir., 2023)

    In re Couvaras, 22-1489, 2023 WL 3984753 (Fed. Cir., June 14, 2023)

    Precedential Opinion by Circuit Judge Lourie; joined by Circuit Judges Lourie, Dyk, and Stoll

    The United States Court of Appeals for the Federal Circuit (CAFC) agreed with the Patent Trial & Appeals Board (PTAB), and the USPTO examiner, that claims in U.S. Patent Application No. 15/131,442 (US2016/228,393), which recites methods of increasing prostacyclin release in the systemic blood vessels of a human with essential hypertension to improve vasodilation, were obvious because the claims relate to combatting hypertension with known antihypertensive agents and merely disclose their previously unappreciated mechanism of action.”

    High Level Summary

    The prior art taught that GABA-a agonists and ARBs reduce anti-hypertension. Dr. Couvaras discovered that GABA-a agonists and ARBs reduce anti-hypertension, in part, because they increase prostacyclin and promote vasodilation. Dr. Couvaras applied for a patent claiming a method of increasing prostacyclin in an individual with hypertension to improve vasodilation by providing an ARB and a GABA-a agonist.  However, the USPTO rejected the claims because the element of increasing prostacyclin was inherent in the well-known prior art method of independently treating hypertension with an ARB or a GABA-a agonist. 

    Visualizing the case with diagrams

    Now let’s skeletonize the elements of this case down to arrow diagrams. We don’t need too many facts getting in the way of this good story. 🙂 *

    Claim 11 (abridged): A method of increasing prostacyclin in an individual with hypertension to improve vasodilation by providing an ARB and a GABA-a agonist. 

    A = Providing an ARB and a GABA-a agonist 

    X = Increasing prostacyclin

    B = Vasodilation (treating hypertension)

    * But seriously, although I am scientist reluctant to loose any nuance, technical terms such as Angiotensin II Receptor Blocker (“ARB”) can be distracting in analyzing the the law in case.  Also, I believe that knowing the claims recite a combination therapy is superfluous and thereby distracting itself. (At least I found them distracting at first. Maybe that’s just me. Please work with me for now.) The CAFC’s rule of law works for both mono and combo therapies. See below for a discussion regarding combination therapies.

    The overall goal is to get from A to B. Doctors already know how to get from A to B. It is prior art. No argument there. Then an inventor discovers that X is the mechanism of action that leads to B.

    Doctors did not already know that going from A to B involves X. This is not taught in the prior art.  A→X is a genuine new discovery. No argument there either.

    Now you have  A→ X→ B.

    Although the discovery of A→ X is indeed new, inventors should not be able to patent a claim to the discovery. Even though doctors did not know it, doctors were inherently doing the process of A→ X→ B by simply prescribing A to treat B.  It makes sense that someone should not be able to patent a claim to  A→ X→ B, or even simply A→X, then suddenly prevent doctors from prescribing A→ B, which they have been doing all along.

    New methods and mechanisms of action may still be patented

    In re Couvaras, however, does not mean that all mechanisms and new uses are not patentable. New uses for old compounds May still be patentable. For example, an inventor may discover that A also renders the benefit of C, and that A affects B by going through mechanism Y.

    In this example, the inventor may be able to patent a claim to A→C.

    If an inventor simultaneously discovers that A→C goes through the mechanism “Y” then they may be able to patent a claim covering both A→C, A→Y,  and A→Y→C.  

    NOTE: The inventor should file both claims simultaneously so the inventor’s disclosure of A→C does not block the claim to A→Y. If not, then the inventor will have the same problem from In re Couvaras.

    In summary, patentability of mechanisms (X/Y) rest on the whether the overall benefit (B/C) is unexpected from the known composition (A).

    Secondary Considerations

    Of course, secondary considerations provide some leniency. But the secondary considerations surely need to be compelling.

    “To establish unexpected results, Couvaras would have needed to show that the co-administration of GABA-s agonist and an ARB provided an unexpected benefit,” such as, e.g., better control of hypertension or less toxicity.

    Failure of others: “The purported failure to achieve prostacyclin increase through pursuing an unrelated goal did not establish the non-obviousness of the claimed method.”

    No long felt need: The anti-hypertensive agents were admitted to be available already.

    “The pending claims of the ’422 application literally recite methods of increasing prostacyclin release in the systemic blood vessels of a human with essential hypertension to improve vasodilation. That increased prostacyclin release is achieved by co-administering two well-known types of antihypertensive agents: a GABA-a agonist and an Angiotensin II Receptor Blocker (“ARB”). In reality, the claims relate to combatting hypertension with known antihypertensive agents and claiming their previously unappreciated mechanism of action.”

    Novelty vs. Obviousness: Inherency

    Q: Why is inherency in a case about obviousness and not about novelty?

    A: Here is where the combo-therapy aspect comes in. A combination of two known compounds that render the same benefit is obvious. Dr. Couvaras argued that the discovery of the compounds’ mechanism of action overcame the obviousness rejection. Essentially the argument tried to convince the examiner that each mono therapy was novel. With two novel monotherapies in hand, reasoning follows that combination of two novel monotherapies would have been non-obvious.

    Post Script

    On bright side, The USPTO awarded Dr. Couvaras with U.S. Patent No. 9,339,542 in his earlier application. Composition claims to combinations were non-obvious.

    Granted Claim 1:  A composition effective to relax Smooth muscles in an individual in an altered state, the composition comprising: a dosage of GABA or GABA-a analogue; and a dosage of at least one of an ACE inhibitor and a ARB combined with the dosage of GABA or GABA-a analogue into a deliverable form.

    Amgen Throws Patent Attorneys Under Bus

    “Chemists would not routinely rely on the statements of patent lawyers.”

    Amgen v. Sandoz, 22-1147 (CAFC, 2023)

    Please pardon my delay in posting. I needed to check my wall to see if my diploma was still hanging there. Yes, it is still there. Like many of my fellow patent attorneys, I have a PhD in chemistry. Being a patent attorney and a chemist is not mutually exclusive. To be fair, my laboratory technique might be quite rusty after 20 years behind a desk. But I still consider myself 100% a chemist.

    Twice, Amgen’s litigators successfully argued that Amgen’s own patent prosecutors were wrong and should be ignored. First, Amgen persuaded the court to ignore disclosure in the patent application specification regarding purification processes using crystallization. Second, Amgen persuaded the court to ignore statements that their European Council made to the European Patent Office (EPO) regarding which products resulting from Example 2 of Amgen’s U.S. Provisional Application 60/366,515.

    Patent attorneys often worry about potential adverse statements that anybody makes during prosecution of patent applications. Keep statements and arguments minimal because, once in writing, you cannot take them back. This case appears to be a rare exception. Depending on whose side you’re on, perhaps it is refreshing that cases such as this show that potentially detrimental statements may be ignored once in a while provided the right evidence.

    Otezla® (apremilast) ANDA litigation

    Background

    Apremalist is an optically pure dextrorotary “(+)” enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, having its
    stereo center in the “S” conformation. Stereoisomers regarding apremalist are a big deal because of their similarities to thalidomide.

    The dispute arose from Sandoz’s filing an Abbreviated New Drug Application (ANDA) to sell a generic version of Amgen’s Otezla® (apremalist), a PDE-4 inhibitor used for treating psoriasis.

    Amgen then sued Sandoz to enforce, among others, U S. Patent 7,427,638 claiming a pharmaceutical composition comprising the (+) enantiomer, and U.S. Patent 10,092,541 claims a crystalline solid form of the (+) enantiomer (Form B).

    There were several other issues in this opinion. One that I have spent much time considering is the issue of patenting of stereoisomers.  Look out for my subsequent post to the page “Obviousness of Stereoisomers & Purified Compounds” regarding the decision in this case.

    Priority Claim

    U S. Patent 7,893,101 claims priority to earlier provisional patent application 60/366,515. Sandoz argued that the priority claim was invalid because Example 2 in the provisional application, instead of making only crystalline Form B, also made Form C. Sandoz cited as evidence Amgen patent council’s statements to the EPO stating that Example 2 made both forms. However, counsel’s statement was wrong because Example 2 indeed only made Form B. Amgen was allowed to present data to prove it, including thirteen third-party experiments. With the data as evidence, Amgen was able to take back their erroneous, detrimental statement.

    Non-Obviousness

    Sandoz argued that Amgen’s claims to optically pure compound were obvious because statements in the specification about the separation of the enantiomers. The Statements made the process of isolating enantiomers sound routine. However, Amgen was able to persuade the court that isolating the (+) enantiomer was not routine because, contrary to the specification, formation of chiral salts was not viable. In other words, oversimplified colloquially, the patent attorney drafting the application made the invention sound too easy describing techniques that real chemists would know actually would not work.

    Gilead Wins Another Sofosbuvir Challenge: U. Minnesota v. Gilead

    Regents of the U. of Minnesota v. Gilead Scis., Inc., 2021-2168, — F.4th — (Fed. Cir. Mar. 6, 2023)

    The Court of Appeals for the Federal Circuit (CAFC) analyzed whether the written description found in UMN’s priority applications supported the claims in the resulting patent # US 8,815,830. The CAFC said no.

    While the ‘830 patent claims covered sofosbuvir, The CAFC affirmed an IPR’s invalidation of U. Minnesota’s claims because they could not properly claim priority to its provisional application. The reasoning was that the provisional with its nebulous multiple dependent claims, that were themselves dependent on further multiple dependent claims, did not adequately describe the subgenus eventually claimed in the non-provisional application.

    See Patently-O’s posts for more:

    March 7, 2023 — Laundry Lists of Components are Insufficient Written Description for a Particular Combination | Patently-O (patentlyo.com)

    March 9, 2023 — Multiple dependent claims, blaze marks, and ipsis verbis support | Patently-O (patentlyo.com)

    SOVALDI® (soh-VAHL-dee) (sofosbuvir)



    Supreme Court Sizes Up the Genus – Enablement

    The Supreme Court of the United States (SCOTUS) is set to hear arguments on Monday, March 27, 2023 for Amgen v. Sanofi.

    ACS’s Chemistry and the Law (CHAL) Division weighs in

    The American Chemical Society’s Chemistry and the Law (CHAL) division filed an Amicus brief supporting Amgen’s petition and reversing the Federal Circuit’s decision. Indeed, the resolute CHAL even petitioned the court to get 5 minutes to participate in arguments.

    Stay Tuned!

    Amgen Inc. v. Sanofi – SCOTUSblog

    Amgen’s X-Ray crystallography studies of antibodies 21B12 & 31H4 bound to PCSK9

    Idenix v. Gilead: Split CAFC Panel at Least Agrees – Valid or Not, Either Way it’s Idenix Loss – Claims Too Broad

    Idenix Pharmaceuticals LLC v. Gilead Sciences Inc. (Fed. Cir. 2019); 941 F.3d 1149 (2018 WL 922125) CAFC Panel: Chief Judge Prost and Circuit Judges Newman and Wallach
    Opinion by Chief Judge Prost; dissenting opinion by Circuit Judge Newman

    Idenix claims invalid / not enabled

    sofosbuvir

    Background: Idenix’s sued Gilead claiming Gilead’s sofosbuvir (Solvadi®) HCV treatment would infringe U.S. Patent No. 7,608,597, directed to methods for treating hepatitis C virus (HCV). Gilead argued that they should not be liable for infringement because the ‘597 patent was not valid since the patent’s specification did not enable the claims. At first, a jury at the district court level said that the claims of the ‘597 patent were enabled and therefore valid. However, the district court judge disagreed and granted Gilead’s Motion for a Judgment as of Matter of Law (JMOL), overruling the jury. When Idenix appealed, the United States Court of Appeals for the Federal Circuit (CAFC) affirmed the district court’s decision, agreeing that the ‘597 patent was invalid and therefore Gilead was not liable for infringement. In the end, the U.S. Supreme Court refused to hear the case [cert. denied, 141 S. Ct. 1234 (2021)].

    CAFC Panel Split: In the Opinion, Chief Judge Prost and Circuit Judges Wallach agreed that Idenix’s ‘597 patent claims were not enabled. Circuit Judge Newman dissented, arguing that the ‘597 patent, although having overly broad claims, was still valid. However, while still valid, the claims should be interpreted narrowly, allowing Gilead to avoid liability anyway.

    Common Ground: Let’s focus upon where all three judges agreed – Idenix should loose. While much attention has been given to how the panel was split as to whether the ‘597 patent was valid or not, we should remind ourselves that all three at least agreed that Gilead should not be liable for infringement. All three judges appeared to agree that Idenix’s claims were too broad. They diverged on how to get Gilead off the hook.

    Loss either way:

    (1) Majority – Rule that the claims are invalid by lack of enablement.

    (2) Dissent – Rule that the claims are valid but not enforceable.

    Forward to Amgen vs. Sanofi:

    Circuit Judge Lourie’s Opinion in AMGEN INC. v. SANOFI, No. 20-1074 (Fed. Cir. 2021) referenced Idenix in concluding that Amgen’s claims were invalid as non-enabled.

    The Supreme Court of the United States is set to hear arguments in Amgen on March 27, 2023. Stay tuned!

    If you get a restriction requirement, then use it to file divisionals.

    January 29, 2018

    Worried about Obviousness-type Double Patenting?: If you get a restriction requirement, then use it to file divisionals. 

    Since the “Gilead case,” many of us worry about terminal disclaimers for Obviousness-type Double Patenting erasing any Patent Term Adjustment.  With Divisional applications that worry should be abated since 35 U.S.C 121 has been interpreted to prohibit claims in a divisional application (filed following a restriction requirement) from being cancelled or rejected based upon the parent application.

    IMPORTANT: For you to use the safety net of 35 U.S.C 121, you need to file a divisional application.

    • File New Application, in view of the restrition requirement, as a Divisoinal
    • You cannot simply file a new continuation or continuation-in-part and then take advantage of 35 U.S.C 121.
    • You cannot go back and fix your continuation by trying to convert it to a divisional.
      • J&J / NYU tried this with their Remicade patents and it didn’t work.

    Remicade case:

    Take home message: The “CIPs” in the graphic below should have been “Divisionals.”

    Patently-O Post:

    https://patentlyo.com/patent/2018/01/patent-blockbuster-remicade.html

    Rothwell, Figg Post:

    http://www.ptablaw.com/2018/01/30/strict-limits-3-u-s-c-§-121s-safe-harbor-provision-intersection-two-blogs/

     

    Velcade® Patent Validated by CAFC

    August 8, 2017

    Millennium Pharmaceuticals, Inc. v. Sandoz Inc. (Fed. Cir. 2017)

    A Court of Appeals for the Federal Circuit (CAFC) panel reversed the district court’s holding that Millennium’s licensed patent, U.S. Patent No. 6,713,446 (“the ‘446 Patent”) was invalid for being obvious. The ‘446 Patent claimed a lyophilized mannitol ester prodrug of Bortezomib (See Claim 20). Claim 20 was not obvious according to the panel because, among other reasons, the inventors unexpectedly “discovered that the reason for the dramatic improvement in dissolution and stability for this formulation was the formation of a new chemical compound during lyophilization: the claimed ester of bortezomib and mannitol.”

    • Claim 20:  The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

    Earlier, the district court concluded that the new compound was obvious reasoning that Bortezomib was already known (U.S. Patent No. 5,780,454), Lyophilization is already known known, and that the claimed compound is “the inherent result of an allegedly obvious process” of  lyophilizing bortezomib and mannitol together.

    • There was no evidence that anyone “foresaw, or expected, or would have intended, the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought properties and advantages”
    • “The district court did not find that the prior art taught or suggested that the claimed new compound would be formed, or taught or suggested making the claimed new compound by any method, or taught or suggested that this new compound would have the properties of stability, solubility, and dissociability that it exhibited.”
    • “No reference taught or suggested reacting bortezomib with mannitol, and no reference hinted that such an esterification reaction might occur during lyophilization.”
    • “No reference taught or suggested that the product of such lyophilization would be a new chemical compound that would solve the problems that had inhibited development of bortezomib in oncology.”
    IP Watchdog Post by Jay Pattumudi:
    http://www.ipwatchdog.com/2017/08/10/inherent-obviousness-motivation-modify-lead-compound-surprising-unexpected-results/id=86661/
    Patent Docs Post:
    http://www.patentdocs.org/2017/07/millennium-pharmaceuticals-inc-v-sandoz-inc-fed-cir-2017.html
    Dilworth IP Post:
    http://www.dilworthip.com/nonobviousness-push-back-millennium-pharma-v-sandoz/
    VELCADE® Prescribing Information:
    http://www.velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf
    VELCADE® (bortezomib) Official Website:
    http://www.velcade.com/

    Recent Doctrine of Equivalence Case: “Insubstantial Differences” Test May Be More Suitable than a “Function-Way-Result” Test for Chemical Arts.

    The Doctrine of Equivalence is alive and well.  For the chemical arts, the CAFC recently suggested that the “Insubstantial Differences” test may be more suitable than a “Function-Way-Result” Test.

    See Christopher E. Loh’s post for Fitzpatrick, Cella, Harper & Scinto