Diamyd Medical ABDownload PDFPatent Trials and Appeals BoardJun 29, 20212020006074 (P.T.A.B. Jun. 29, 2021) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/315,557 12/01/2016 Anders ESSEN-M¿LLER ZACCO-008 9980 93726 7590 06/29/2021 EPA - BOZICEVIC FIELD & FRANCIS LLP BOZICEVIC, FIELD & FRANCIS 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER EWOLDT, GERALD R ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 06/29/2021 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ANDERS ESSEN-MÖLLER and JOHNNY LUDVIGSSON Appeal 2020-006074 Application 15/315,557 Technology Center 1600 Before DONALD E. ADAMS, FRANCISCO C. PRATS, and RACHEL H. TOWNSEND, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 87, 89–93, and 98–100. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as Diamyd Medical AB. Appeal Br. 3. Appeal 2020-006074 Application 15/315,557 2 CLAIMED SUBJECT MATTER Appellant’s invention is directed to “to the prevention and/or treatment of autoimmune diseases such as type 1 diabetes or autoimmune diabetes.” Spec. 1. The Specification explains that, “[i]n autoimmune disease, the adaptive immune system commonly reacts to at least one self- antigen, (auto-antigen, aag).” Id. The Specification discloses that “[l]arge clinical trials have been performed and are currently being performed using different insulin derived formulations in order to induce tolerance and stop or prevent the disease progression.” Spec. 2. The Specification discloses that “[m]any other beta cell antigen molecules and peptides thereof including but not limited to GAD65 have been tried for the same purpose, and others, not limited to insulin B-chain and pro-insulin and variations thereof, are being prepared for clinical development.” Id. The Specification explains that “GAD65 (the 65 kd isoform of Glutamic Acid Decarboxylase), is a major beta cell auto-antigen, as it is produced in the islets with increased release as response to beta cell stimulation. This protein has been shown to deeply influence the autoimmune immune process.” Spec. 7. In particular, “[n]umerous studies have shown that GAD can prevent diabetes in experimental animals.” Id. The Specification discloses that clinical trials involving “GAD-alum (Diamyd)” led to the conclusion that “that while partly effective, GAD-alum may need to be combined with other compounds in order to become part of a clinically effective treatment regimen for type 1 diabetes.” Spec. 7. Appellant’s claim 87 is representative of the appealed subject matter and reads as follows: Appeal 2020-006074 Application 15/315,557 3 87. A method for treating at least one of type 1 diabetes, autoimmune diabetes, and latent autoimmune diabetes, comprising administering to a subject in need thereof a therapeutic composition comprising at least one β cell autoantigen and alum, wherein the at least one β cell autoantigen is glutamic acid decarboxylase (GAD), the administering is done by injection directly into a lymph node and the subject has a serum vitamin D level that is above 50 nanomole/litre. Claims App. 2 (Claims Appendix entered May 1, 2020; indentation added). REJECTION(S) The sole rejection before us for review is the Examiner’s rejection of claims 87, 89–93, and 98–100 under 35 U.S.C. § 103 as being unpatentable over the Diamyd Press Release2 and Senti.3 Ans. 3–4. DISCUSSION The Examiner’s Prima Facie Case The Examiner found that the Diamyd Press Release discloses a process differing from the process recited in Appellant’s representative claim 87 “only in that it does not teach administration of the GAD by intra- lymph node injection.” Ans. 3. 2 Diamyd Press Release, “New clinical study with Diamyd diabetes vaccine,” (http://www.diamyd.com/docs/pressClip.aspx?section=investor& ClipID=738265) (2013) (citation provided in Information Disclosure Statement filed March 23, 2017). 3 Gabriela Senti et al., Intralymphatic allergen administration renders specific immunotherapy faster and safer: A randomized controlled trial, 105 PNAS 17908–17912 (2008). Appeal 2020-006074 Application 15/315,557 4 The Examiner found, however, that Senti teaches “intra-lymph node administration of an antigen for the induction of tolerance to said antigen.” Ans. 3. Based on the references’ combined teachings, the Examiner concluded that it would have been obvious to treat type 1 diabetes “through the method of the Diamyd Press Release wherein the administration of the GAD65 antigen in combination with alum, ibuprofen, and vitamin D was by intra-lymph node injection given the teachings of Senti et al. that intra- lymph node injection of antigens facilitates tolerance to said antigens.” Ans. 3–4. The Examiner reasoned that using intra-lymph node injection to perform the process described in the Diamyd Press Release “is supported by sound scientific reasoning as it was well known at the time of filing that naïve T cells first encounter antigen in the lymph nodes thus, direct injection therein would have been expected to have been more efficient.” Ans. 4. The Examiner noted in particular that “[s]uch results were shown by Senti et al. in that the tolerance was shown to result faster and be longer lasting.” Id. As to the requirement in representative claim 87 for the subject to have a serum vitamin D level above 50 nanomole/liter, the Examiner noted “vitamin D’s tolerogenic properties (as cited in the specification)” as well as the fact that the process of the Diamyd Press Release includes administration of vitamin D, such that a subject of that process “would be expected to achieve at least a 50 nmol/L serum concentration after a first treatment given that a minimum recommended serum level of vitamin D is approximately 125 nmol/L.” Ans. 4. Appeal 2020-006074 Application 15/315,557 5 Analysis [T]he examiner bears the initial burden . . . of presenting a prima facie case of unpatentability. . . . After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992); see also In re Jung, 637 F.3d 1356, 1365 (Fed. Cir. 2011) (holding that requiring an applicant to identify “reversible error” in an examiner’s rejection is consistent with long standing Board practice). Having carefully considered all of the evidence and argument presented by Appellant and the Examiner, we are not persuaded that Appellant has shown reversible error in the Examiner’s conclusion of obviousness as to Appellant’s representative claim 87. The Diamyd Press Release describes an FDA-approved clinical study which “combines the diabetes vaccine Diamyd ® with relatively high doses of vitamin D and the anti-inflammatory drug ibuprofen. The aim of treatment is to preserve the body’s own ability to regulate blood sugar in children and adolescents with recent-onset type 1 diabetes.” Diamyd Press Release 1.4 The Diamyd Press Release explains that “[t]ype 1 diabetes . . . is an autoimmune disease which means that the body’s own immune system attacks and destroys the cells in the body that produce insulin, the so-called beta cells in the pancreas leading to insulin deficiency and inability to 4 The Diamyd Press Release does not include page numbers. We cite to document as if the pages were numbered consecutively starting with page 1. Appeal 2020-006074 Application 15/315,557 6 control blood sugar levels.” Diamyd Press Release 2. The Diamyd Press Release explains that the clinical trial’s treatment with the GAD-containing Diamyd vaccine “is designed to prevent, delay, or stop the autoimmune attack on beta cells.” Id. It is undisputed on this record that the Diamyd vaccine contains alum as well as GAD, as recited in Appellant’s claim 87. See Spec. 7 (describing previous clinical trials involving “GAD-alum (Diamyd)”). It is also undisputed on this record that patients receiving the vitamin D dosage described in the Diamyd Press Release will have a serum vitamin D level that is above 50 nanomole/liter, as also recited in Appellant’s claim 87. As required by Appellant’s claim 87, the Diamyd Press Release discloses that the Diamyd is administered by injection. See Diamyd Press Release 2 (describing different treatment groups receiving “an injection of Diamyd ®”). Thus, as the Examiner found, and Appellant does not dispute, the sole difference between the process described in the Diamyd Press Release and the process recited in Appellant’s claim 87 is that the Diamyd Press Release does not disclose that the GAD-alum composition (the Diamyd vaccine) is injected directly into the lymph node. We agree with the Examiner that, when performing the process taught in the Diamyd Press Release, it would have been obvious to inject the Diamyd vaccine directly into the lymph node. As the Examiner found, Senti discloses that direct injection into the lymph node of hay fever-causing antigens induced superior tolerance as compared to standard subcutaneous (“s.c.”) injections, and also had several other advantages: Appeal 2020-006074 Application 15/315,557 7 Three low-dose intralymphatic allergen administrations increased tolerance to nasal provocation with pollen already within 4 months (P < 0.001). Tolerance was long lasting and equivalent to that achievable after standard s.c. immunotherapy (P = 0.291 after 3 years). Intralymphatic immunotherapy ameliorated hay fever symptoms (P < 0.001), reduced skin prick test reactivity (P < 0.001), decreased specific serum IgE (P < 0.001), caused fewer adverse events than s.c. immunotherapy (P = 0.001), enhanced compliance (P < 0.001), and was less painful than venous puncture (P = 0.018). In conclusion, intralymphatic allergen administration enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks. Senti 17908; see also id. at 17910–17911 (“We demonstrated that intralymphatic allergen administration enhanced safety, efficacy, and compliance of s.c. immunotherapy and allowed reduction of the number of injections from 54 to 3, and reduction of the cumulative allergen dose by more than 1000-fold.”) Senti goes on to teach that, beyond the allergic tolerance examined in its study, “intralymphatic injection appears to generally enhance the efficacy of vaccination and immunotherapy. The explanation is that only a small fraction of s.c.-injected biomolecules reaches the draining lymph nodes to stimulate the immune response, whereas direct injection into a lymph node delivers all of the vaccine to the lymphatic organ.” Senti 17911. Thus, on the current record, the Diamyd Press Release describes injecting patients with the GAD-containing Diamyd vaccine to prevent an attack by the patients’ immune system on its own pancreatic beta cells, that is, to induce immune tolerance to the GAD protein so that the patients’ immune system does not attack its own beta cells. Senti, in turn, teaches that intralymphatic injection is useful for inducing immune tolerance to hay fever Appeal 2020-006074 Application 15/315,557 8 antigens, has a number of advantages as compared to standard s.c. injections of antigens for immunotherapy, and generally enhances the efficacy of vaccination and immunotherapy. Given these teachings, we agree with the Examiner that a skilled artisan, injecting the Diamyd vaccine into patients as taught in the Diamyd Press Release, had a good reason for, and a reasonable expectation of success in, injecting the Diamyd vaccine directly into the patients’ lymph nodes, as taught in Senti. We therefore also agree with the Examiner that a skilled artisan would have considered the process recited in Appellant’s claim 87 prima facie obvious. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“[I]f a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”). Appellant’s arguments do not persuade us to the contrary. Appellant argues that allergies and autoimmune diseases are entirely different phenomena, and therefore “there is no reasonable expectation that something that might work for allergies (e.g., Senti’s intra-lymph node administration method) would also be expected to work for Type I diabetes.” Appeal Br. 9; see also Reply Br. 2 (“There is simply no nexus between treatment of allergies and treatment of autoimmune disease in the cited prior art and, as such, there is no reason to expect that Senti’s method would work for an aut[o]immune disease.”). We are not persuaded. We first note, as the Examiner contends, and as Appellant does not dispute, “any immunologist of ordinary skill in the art would have known at the time of filing, lymph nodes are where immune responses happen. As Appeal 2020-006074 Application 15/315,557 9 taught by Senti et al., they employed lymph node injection because it had worked in other immunological contexts.” Ans. 6; see also Senti 17910 (disclosing that “[e]nhanced efficacy of targeted lymph node immunization has also been found for immunostimulatory complexes, bacteriophages, and a recombinant simian immunodeficiency virus vaccine” and therefore that “intralyrnphatic injection appears to generally enhance the efficacy of vaccination and immunotherapy,” the explanation being that “only a small fraction of s.c.-injected biomolecules reaches the draining lymph nodes to stimulate the immune response, whereas direct injection into a lymph node delivers all of the vaccine to the lymphatic organ”). Given the variety of useful immunological contexts of intralymphatic injection, and given Senti’s teaching that intralymphatic injection generally enhances vaccine and immunotherapy efficacy, Appellant does not persuade us that a skilled artisan lacked a reasonable expectation of success in using intralymphatic injection in the process described in the Diamyd Press Release. As our reviewing court has explained, “[o]bviousness does not require absolute predictability of success. . . . For obviousness under § 103, all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (quoting In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988) (emphasis removed) (alteration in original). Moreover, as discussed above, the nexus between treating type 1 diabetes as taught in the Diamyd Press Release, and treating allergies as taught in Senti, is that both treatments involve administration to a patient, by injection, of an antigen that causes an undesired immune/inflammatory response. See Diamyd Press Release 2 (explaining that the clinical trial’s treatment with the GAD-containing Diamyd vaccine “is designed to prevent, Appeal 2020-006074 Application 15/315,557 10 delay, or stop the autoimmune attack on beta cells”); see also Senti generally (injecting extracts of hay fever allergens to inhibit allergies). Indeed, in discussing the background state of the art, Appellant’s own Specification explains that the art-recognized objective of administering GAD was to induce tolerance. See Spec. 2 (disclosing that “[l]arge clinical trials have been performed and are currently being performed using different insulin derived formulations in order to induce tolerance and stop or prevent the disease progression” and that “[m]any other beta cell antigen molecules and peptides thereof including but not limited to GAD65 have been tried for the same purpose”) (emphasis added). We are also not persuaded that Appellant has advanced evidence sufficient to support its contention that a skilled artisan would have believed that Senti’s intralymphatic injection technique “does not work even for treating allergies.” Appeal Br. 12; see also id. at 10–11 (citing Witten);5 Reply Br. 3. We acknowledge Witten’s teaching, identified by Appellant, that in its experiments intralymphatic injection “for grass pollen allergy revealed no improvement in patients’ registered symptoms and use of rescue medication or in quality-of-life or intradermal test scores in spite of weak signs of immune modulation of IgE and IgG4.” Witten 1251. As the Examiner points out, however, rather than stating that intralymphatic injection does not work, Witten ultimately concludes that more study of the technique is required: 5 Marianne Witten et al., Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?, 132 J. ALLERGY CLIN. IMMUNOL. 1248–1251 (Letter to the Editor) (2013). Appeal 2020-006074 Application 15/315,557 11 Even though the number of treated patients in our study exceeds the sum of the 2 previous placebo-controlled studies, it was small, and further adequately performed large-scale, double-blind, placebo-controlled studies focusing on optimizing allergen extracts, dose regimens, or both are required before ILIT [intralymphatic immunotherapy] is ready for clinical use. Witten 1251(emphasis added). We are not persuaded that a study whose ultimate conclusion advises further study of a technique, that is, trying it again, is sufficient to teach away from performing the technique. See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009) (“A reference does not teach away . . . if it merely expresses a general preference for an alternative invention but does not criticize, discredit, or otherwise discourage investigation into the invention claimed.”) (citation and internal quotation marks omitted). Indeed, by advising further study, Witten encourages investigation into the invention claimed, rather than discourages it. Moreover, to properly consider the record evidence of obviousness as a whole, Witten’s teaching as to the desirability of further study of intralymphatic injection must be considered alongside the teachings discussed above in Senti, that intralymphatic injection is useful for inducing immune tolerance to hay fever antigens, has a number of advantages as compared to standard injections used in immunotherapy, and generally enhances the efficacy of vaccination and immunotherapy. Thus, viewing the evidence of record as whole, while Witten might have suggested that a skilled artisan would not have been absolutely certain whether Senti’s intralymphatic injection technique would work in the process of the Diamyd Press Release, absolute certainty is not the criterion of obviousness. See Kubin, 561 F.3d at 1360 (“Obviousness does not require absolute Appeal 2020-006074 Application 15/315,557 12 predictability of success. . . . [A]ll that is required is a reasonable expectation of success.”) (citation and internal quotation marks omitted) (emphasis removed). In addition, we find that Appellant’s argument in relation to Witten is generally inconsistent with its initial arguments. Specifically, as seen above, Appellant initially argues that a skilled artisan lacked a reasonable expectation of success in using Senti’s intralymphatic injection technique in the process of the Diamyd Press Release because autoimmune disorders and allergies are entirely different phenomena. Yet, in the arguments relating to Witten, Appellant contends that any alleged negative teachings in Witten about allergy treatment should be credited as being predictive in relation to treating autoimmune diabetes. In sum, for the reasons discussed, Appellant does not persuade us of reversible error in the Examiner’s conclusion that the process recited in Appellant’s representative claim 87 would have been obvious to a skilled artisan. We therefore affirm the Examiner’s rejection of claim 87 over the Diamyd Press Release and Senti. Because they were not argued separately, claims 89–93 and 98–100 fall with claim 87. 37 C.F.R. § 41.37(c)(1)(iv). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 87, 89–93, 98–100 103 Diamyd Press Release, Senti 87, 89–93, 98–100 Appeal 2020-006074 Application 15/315,557 13 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation