The Board of Trustees of the Leland Stanford Junior University

Patent Trials and Appeals Board

Mar 21, 2022

2021002851 (P.T.A.B. Mar. 21, 2022)

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. 15/993,172 05/30/2018 Bahareh Ajami STAN-1399 1802 77974 7590 03/21/2022 STANFORD UNIVERSITY OFFICE OF TECHNOLOGY LICENSING BOZICEVIC, FIELD & FRANCIS LLP 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER ULM, JOHN D ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 03/21/2022 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 BAHAREH AJAMI and LAWRENCE STEINMAN Appeal 2021-002851 Application 15/993,172 Technology Center 1600 Before TAWEN CHANG, JOHN E. SCHNEIDER, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims to a treatment of amyotrophic lateral sclerosis (ALS) by reducing the activity of CD49e+ myeloid cells by administering a blocking antibody that specifically binds to human integrin α5 as failing to meet the enablement and written description requirements of 35 U.S.C. § 112. 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. Appellant identifies the real party in interest as the Board of Trustees of the Leland Stanford Junior University. (Appeal Br. 2.) Appeal 2021-002851 Application 15/993,172 2 STATEMENT OF THE CASE Appellant’s Specification indicates, regarding “the paradigm of classical inflammation,” that the inflammatory response is defined by the activation of tissue- resident macrophages as the first line of defense and the subsequent recruitment of leukocytes from the blood into the affected tissue. Prominent in this cascade is the migration of monocytes into peripheral tissues to contribute to the inflammatory process and to replenish the resident tissue macrophages. (Spec. ¶ 143.) Appellant’s Specification notes that, “[l]ike inflammation in peripheral tissues, monocyte infiltration has been linked to inflammatory responses in diseases of the central nervous system.” (Id.) Appellant’s Specification states that amyotrophic lateral sclerosis (ALS) “is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement.” (Spec. ¶ 73.) Appellant’s Specification states that ALS is “not traditionally classified as an inflammatory disease,” (id. ¶ 64) and “there is no evidence of the same classical inflammatory response” of infiltration of peripheral adaptive and innate immune cells as in multiple sclerosis (MS)2 (id. ¶ 115), but further states that ALS “has been found to have increased numbers of CD49e macrophages.” (Id. ¶ 64.) CD49e is also known as alpha 5 integrin.3 (Id. ¶ 5.) 2 Appellant’s Specification explains that MS is an inflammatory disease of the brain and spinal cord. (Spec. ¶ 2.) Appellant’s Specification further explains that, in MS, “there is rampant inflammation with migration of peripheral immune cells in the [central nervous system].” (Id. ¶ 115.) 3 “Integrins are heterodimeric transmembrane receptors that mediate cell- adhesion.” (Spec. ¶ 44.) Appellant’s Specification explains that “[f]or many biological processes, most notably hemostasis and immunity, it is important Appeal 2021-002851 Application 15/993,172 3 Appellant’s invention is directed at a method of using, as a treatment for ALS, blocking antibodies to CD49e/human alpha 5 integrin in patients having ALS. (Spec. ¶¶ 9, 64, 77.) Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A method to stabilize or reduce the clinical symptoms of amyotrophic lateral sclerosis (ALS) by reducing the activity of CD49e+ myeloid cells in the central nervous system in a patient, the method comprising: administering to said patient a therapeutically effective dose of a blocking antibody that specifically binds to human integrin α5 and reduces the activity of CD49e+ myeloid cells. (Appeal Br. 14.) The following grounds of rejection by the Examiner are before us on review: Claims 1, 2, 8-10, and 14-24 under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement. Claims 1, 2, 8-10, and 14-24 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. that integrin-mediated adhesion can be regulated.” (Id. ¶ 45.) “[B]lock[ing] . . . the entry of peripheral immune cells to the brain with antibodies to key integrins has served as the mechanistic basis for the most potent approved therapy, approved [for treating MS].” (Id. ¶ 115.) Appeal 2021-002851 Application 15/993,172 4 DISCUSSION I. Lack of Enablement A. Enablement Rejection The Examiner found a lack of enablement for the claimed method because (a) there is not a working example of administering the claimed antibody to a person with ALS (Final Action 3); (b) there is not a working example of administering the claimed antibody in “an animal model in which there is an established correlation between the efficacy of a therapeutic protocol in the treatment of that model and efficacy in the treatment of a human subject afflicted with ALS” (id.); and, (c) the Specification “fails to provide evidence of a demonstrated in vivo or in vitro activity for the claimed method in combination with evidence that such activity was known to be reasonably predictive of the efficacy of a therapeutic protocol in the treatment of ALS in a human subject” (id.). The Examiner explained that the single example provided in the Specification related to ALS found at pages 46 and 47 (Example 34) is a “characterization of CD49e expression by microglia[5] in mSOD1[6] mice.” 4 The Examiner mistakenly refers to this example as Example 4 at page 4 of the Final Action. 5 Microglia is an immune cell in the CNS. (Spec. ¶ 115.) 6 SOD1, superoxide dismutase 1, is a “cytoplasmic and mitochondrial enzyme which functions in a dimeric state to catalyse the breakdown of harmful reactive oxygen species.” (Spec. ¶ 76.) The SOD1 gene is found on chromosome 21 and missense mutations in it “were the first identified cases of autosomal dominant F[amilial] ALS.” (Id.) Certain mice have been Appeal 2021-002851 Application 15/993,172 5 (Final Action 4; see also id. at 5.) The Examiner pointed out that this Example “is completely silent of any beneficial results obtained from the administration of an anti-CD49e antibody” (Id. at 5). The Examiner thus found that “there is no animal model for ALS which has been employed by Applicant to test the claimed method.” (Id.) The Examiner also explained that a previous office action provided in detail, and with prior art support, why the “EAE7 data described in Example 1 on pages 24 to 43 of the . . . specification . . . does not correlate to therapeutic efficacy in the treatment of ALS” 8 and noted that “Applicant has provided no evidence to the contrary.” (Final Action 5-6 (referencing the office action mailed June 20, 2019).) The Examiner explained that the EAE engineered to over-express human mutant superoxide dismutase 1. (Id. ¶ 28, 187.) 7 EAE stands for Experimental Autoimmune Encephalomyelitis. As stated in the Specification, the EAE mouse model is a model of MS. (Spec. ¶ 114.) 8 The Examiner indicated that there is not even a “reasonable correlation between the efficacy of a therapeutic protocol in the treatment of EAE and efficacy in the treatment of MS.” (June 20, 2019 Office Action 7.) The Examiner noted that the model “mimics only certain pathological manifestations of MS and is causally unrelated thereto.” (Id.) After quoting from, and discussing the import of, numerous publications, the Examiner explained: Whereas EAE animals are routinely employed in the identification of compounds that inhibit autoimmune demyelination such as occurs in ADEM and AHLE, for which it is an art-accepted model, the overwhelming evidence of record shows that the ability of a therapeutic protocol to inhibit demyelination in an EAE animal does not place in the hands of the skilled practitioner a method of inhibiting demyelination in a human suffering from MS. (Id. at 10.) This discussion is provided in the Answer as well. (Ans. 6-12.) Appeal 2021-002851 Application 15/993,172 6 model “is not considered to be an art-accepted model of ALS at all.” (Ans. 12.) In addition to the foregoing, the Examiner found that “there is no evidence of an established reasonable correlation between any particular in vitro activity and efficacy in the treatment of ALS in a human subject.” (Final Action 4.) The Examiner also referenced two publications (DiBernardo et al.9 and Benatar10) in addressing why the example using the SOD1 mouse model to characterize ALS in humans “provides absolutely no evidence that the administration of an anti-human integrin α5 antibody to a human subject afflicted with ALS will provide benefit thereto.” (Final Action 4; Ans. 4.) The Examiner further found that “the DiBernardo et al. and Benatar publications clearly show that one of skill in the art of neurobiology can not predict, ‘by resort to known scientific law’, the operability of a method of treating ALS until operability of the method has actually been demonstrated.” (Final Action 5.) The Examiner also reiterates that the Specification does not describe an experiment “using an animal model for ALS . . . to test the claimed method.” (Id.) The Examiner noted DiBernardo acknowledges that the SOD1 mouse model SOD1G93A is “‘primarily used for therapeutic research’” and that it “‘generally recapitulates human disease, including cardinal finding of motor neuron loss, microgliosis and astrocytosis.’” (Ans. 4 (quoting DiBernardo 9 Allitia B. DiBernardo and Merit E. Cudkowicz, Translating preclinical insights into effective human trials in ALS, 1762 Biochimica et Biophysica Acta 1139-49(2006) 10 Michael Benatar, Lost in translation: Treatment trials in the SOD1 mouse and in human ALS, 26 Neurobiology of Disease 1-13 (2007). Appeal 2021-002851 Application 15/993,172 7 1142).) DiBernardo further states that animal models for ALS have a “major weakness”: The major weakness of animal models for ALS thus far has been the de facto failure of these models to predict response in humans. . . . a number of compounds found to be effective in this model failed in humans, including vitamin E [113], gabapentin [114], topiramate [115], celecoxib [116], and creatine [117]. The reasons for discordant results between mouse and human trials are not fully understood but may relate to inherent differences between the mouse and human disease. (Id. (citing DiBernardo 1142).) The Examiner noted that Benatar echoes the foregoing. (Id. (citing Benatar Abstract and Introduction).) The Examiner recited the following from Benatar: Since the identification of mutations in the SOD1 gene as an important cause of familial ALS (Rosen et al., 1993) and the generation of the SOD1 mouse model of ALS several years later (Gurney et al., 1994), there have been dozens of studies of a panoply of therapeutic agents in SOD1 mice. The choice of therapeutic agents in many clinical trials of human ALS (Cudkowicz et al., 2006; Groeneveld et al., 2003; Shefneret al., 2004) has been predicated, at least in part, on the efficacy of these drugs when studied in the SOD1 mouse (Drachman et al., 2002; Klivenyi et al., 1999). Nevertheless, success in human clinical trials has been extremely limited, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans. (Id.) The Examiner found that, “[c]onsequently, the evidence of record shows that efficacy of a protocol in the treatment of a SOD1 mouse clearly does not correlate to the efficacy of that protocol in the treatment of ALS in humans.” (Ans. 5.) In the Answer, the Examiner summarized the rejection as follows: In summary, the claimed method is not enabled because, whereas one of skill in the art of neurobiology could readily administer a Appeal 2021-002851 Application 15/993,172 8 blocking antibody that specifically binds to human integrin a5 to a human subject afflicted with ALS, the instant specification does not disclose any particular amount of such an antibody that has been shown, or could reasonably be predicted, to stabilize or reduce the clinical symptoms of ALS in that subject. Further, because the specification[] fails to provide any evidence that the administration of a blocking antibody that specifically binds to human integrin a5 to a human subject afflicted with ALS has actually been shown to stabilize or reduce the clinical symptoms of ALS in that subject, one of skill has no reasonable expectation that a ‘therapeutically effective dose’ of such an antibody truly exists. (Ans. 6.) The Examiner further explained that the declarations of Drs. Robert Brown, Gilbert Block, and Stanley Appel that were filed June 26, 2020, as well as the declaration of Dr. Lawrence Steinman that was filed November 20, 201911, were considered but not found to be persuasive to demonstrate the Specification enables the claimed method. (Final Action 7-11; Ans. 17- 18.) The Examiner had two primary points regarding Dr. Brown’s declaration. First, the Examiner noted that while Dr. Brown “discloses how the murine SOD1 system has led to the development of therapeutic protocols,” the declaration provides no evidence that, as of the 30 May 2017 filing date of the instant application, all, or a majority of therapeutic protocols which inhibit neuroinflammatory processes could reasonably be predicted to prevent or retard the progression of ALS in either a 11 We note that the Steinman Declaration is unpaginated. We refer to the first page of that Declaration as page 1, and the remaining pages as if numbered consecutively. Appeal 2021-002851 Application 15/993,172 9 SOD1 mouse or a human afflicted with ALS, and the instant invention has nothing to do with manipulating gene expression. (Final Action 7.) Second, the Examiner explained that, even if he were to concede that there is “a reasonable correlation between the efficacy of a therapeutic protocol in the treatment of ALS in SOD1 mouse and in a human subject,” Dr. Brown “provides no evidence that the skilled artisan in the field of neurobiology can reasonably predict the operability of a theoretical therapeutic protocol for the treatment of ALS based upon observations of changes in cell populations during the progression of ALS in an untreated SOD1 mouse.” (Final Action 8.) Regarding the declaration of Dr. Block, the Examiner noted that he had no dispute with Dr. Block’s statement: “It is a firm fact that in the development of therapeutics for complex and intractable diseases such as ALS, data from preclinical animal models is required to establish a useful mechanism of therapeutic action and to lay the groundwork for future clinical trials.” (Final Action 8.) The Examiner explained, however, that seven publications of record show by a preponderance of the evidence that, with respect to therapeutic protocols for the treatment of neurodegenerative disease such as ALS and multiple sclerosis in particular, positive results in an animal model of a disease more often than not fail to place in the hands of the neurobiologist an operable therapeutic protocol for the treatment of the disease being modeled. (Id.) The Examiner also pointed out that it may be true, as Dr. Block states, that moving forward to human clinical trials is expensive and “patent protection for novel therapeutics” may be important to investors in order for Appeal 2021-002851 Application 15/993,172 10 them to commit to spending millions of dollars to test new therapeutics in humans, but that does not negate the fact that patents are “granted for a complete invention, not an idea and suggestions on how that idea might be developed into something useful,” and Appellant is not seeking patent protection for a therapeutic compound, but to a method of treating ALS. (Final Action 9.) The Examiner explained that such a method requires one to “place in the hands of the routine practitioner of neurobiology the ability to treat a subject afflicted with ALS without the need for substantial further experimentation and inventive contribution.” (Id.) The Examiner argued such is not the case with Appellant’s Specification because [t]he instant specification, at best, describes a method of inhibiting neuroinflammation in an EAE mouse, and there is no evidence of record which supports a position that the description of a method of inhibiting or reducing neuroinflammation in an EAE mouse places in the hands of the skilled neurobiologist the ability to inhibit or reduce neuroinflammation in a subject afflicted with ALS with any reasonable expectation of success. (Id.) Regarding the declaration of Dr. Appel, the Examiner did not dispute Dr. Appel’s statement “‘that studies of therapeutic efficacy in the mSOD1 mouse model of ALS are of considerable value in predicting therapeutic benefit in human ALS’.” (Final Action 10.) However, the Examiner noted that “Declarant provides no evidence that the skilled artisan in the field of neurobiology can reasonably predict the operability of a theoretical therapeutic protocol for the treatment of ALS based upon observations of changes in cell populations during the progression of ALS in an untreated SOD1 mouse.” (Id. at 11.) The Examiner reiterated in this regard that Appellant’s Specification does not provide evidence of administration of an Appeal 2021-002851 Application 15/993,172 11 anti-CD49e antibody to a human afflicted with ALS or even that administration to an SOD1 mouse prevented or retarded the progression of ALS. (Id.) Additionally, the Examiner explained that Dr. Appel provides absolutely no evidence to refute the preponderance of evidence currently of record showing that the vast majority of therapeutic protocols which have been shown to prevent or retard the progression of ALS in SOD1 mice have failed to prove beneficial when applied to the treatment of ALS in humans. (Id. at 10-11.) Regarding the declaration of Dr. Steinman, the Examiner noted that as to the “extensive discussion of the experimental data presented in the instant specification,” such “is not accompanied by evidence of an established correlation between the activity described therein and demonstrated efficacy of a therapeutic protocol possessing that activity in reducing or stabilizing the clinical symptoms of ALS in a human subject.” (Ans. 18.) The Examiner also noted that even as to Dr. Steinman’s urging that the SOD1 mouse is the “‘gold standard’” for ALS research, he does not provide evidence to rebut the position of the Examiner that, as of the 30 May, 2017 filing date of the instant application, no method of treating ALS in a human subject had ever been developed by employing a SOD1 mouse, in spite of the fact that the SOD1 mouse has been employed in this capacity since 1993 and the plurality of therapeutic protocols had been shown to be effective in the treatment thereof had proven to be of no benefit in the treat[]ment of ALS in humans. (Ans. 17-18.) The Examiner also addressed Dr. Steinman’s “discussion of therapeutic protocols entering phase 2/3 clinical trials” which is not presented in the Specification. (Ans. 18.) The Examiner explained that “[e]ntering a clinical trial is not evidence of operability, it is a starting point Appeal 2021-002851 Application 15/993,172 12 through which operability is to be determined.” (Id.) And in particular, the Examiner noted that SOD1 mouse model results provided support for prior art therapeutic protocols for “vitamin E, gabapentin, topiramate, celecoxib and creatin, [which] entered and failed to prove beneficial in the treatment of ALS in humans in phase 2/3 clinical trials.” (Id.) B. Appellant’s Response Appellant’s response is primarily focused on establishing that the SOD1 mouse model “utilized by Appellant[] provides a reasonable model for human testing, and is accepted in the field as providing a useful model.” (Appeal Br. 8.) Appellant refers to the Declaration evidence discussed above and publications to support this assertion. (Appeal Br. 5-7, 11-13). Appellant urges: the “gold standard” animal model in the field is the SOD1 mouse model. The Examiner has, however, rejected data obtained from the use of this animal model, asserting that its use has failed to lead to “a method of reducing or stabilizing the clinical symptoms of ALS in a human subject”. Based on the analysis presented by the Examiner, there is a conundrum. In the absence of any proven therapy for ALS, there can be no proven animal model, and thus there is no possibility of patent protection for methods of treatment, even for promising new therapies that could lead to a therapy for the disease. Appellant[] reject[s] this conundrum, and submit[s] that it is reasonable to obtain patent protection for a therapy that is based on evidence from the best pre-clinical model that is available, even if that pre-clinical model is not perfect. (Appeal Br. 10.) Appeal 2021-002851 Application 15/993,172 13 Appellant also argues that the Examiner’s requirement for positive human clinical trial data is contrary to what the law requires. (Appeal Br. 8- 10.) Appellant also urges that Dr. Brown’s testimony supports that “the animal model utilized by Appellant[] recapitulates important aspects of the human disease, and is deemed an important step in developing a useful therapy.” (Appeal Br. 11.) In addition, Appellant argues that Dr. Appel’s testimony “makes th[e] major point that efforts in his group were based on studies in the mouse model.” (Id. at 12.) And, Appellant notes that “Dr. Block states in his Declaration that the animal data provided by Appellant[] is appropriate for moving forward with further development of human therapy.” (Id.) Appellant concludes that the evidence supports the conclusion that “the therapeutic methods of the present claims, which are based on evidence from an accepted pre-clinical animal model, meet the requirements of 35 USC 112.” (Id.) Appellant contends that in view of the Specification, which contains working examples, and Declaration by Dr. Steinman that Appellant has “provided significant guidance for selection of an antibody for administration,” “the quantity of experimentation needed to make or use the invention based on the content of the disclosure is not undue.” (Id. at 7; see also Reply Br. 2-3.) C. Analysis We agree with the Examiner that the claimed invention is not enabled by Appellant’s Specification. Appeal 2021-002851 Application 15/993,172 14 “The legal question of enablement involves an assessment of whether a patent disclosure would have enabled one of skill in the art at the time the application was filed to make and use the claimed invention without undue experimentation.” Adang v. Fischoff, 286 F.3d 1346, 1355 (Fed. Cir. 2002) (citing Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed.Cir.1986)); In re Swartz, 232 F.3d 862, 863 (Fed. Cir. 2000). Appellant’s application was filed May 30, 2018, but claims benefit to a provisional application that was filed May 30, 2017. As the Examiner recognized, the how to use prong of enablement “incorporates as a matter of law the requirement of 35 U.S.C. § 101 that the specification disclose as a matter of fact a practical utility for the invention.” Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1322-23 (quoting In re Cortright, 165 F.3d 1353, 1356 (Fed. Cir. 1999).) The measure of proof required to establish that practical utility is not simply that the therapeutic method claimed is “not implausible.” Id. at 1325. “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions’ consisting of little more than respectable guesses as to the likelihood of their success.” Id. “[S]uch is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.” Id. Factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the Appeal 2021-002851 Application 15/993,172 15 predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). There is no dispute that claim 1 is directed to a therapeutic method. Claim 1 requires administering, in “a therapeutically effective dose,” a blocking antibody that specifically binds to human integrin α5 (CD49e) and reduces the activity of CD49e+ myeloid cells in the central nervous system of a patient. We conclude that the preamble phrase “to stabilize or reduce the clinical symptoms of [ALS]” provides the only metric by which one practicing the claim could determine whether the administered amount is a therapeutically effective dose. Thus, we conclude the preamble is limiting. See Eli Lilly & Co. v. Teva Pharms. Int’l GmbH, 8 F.4th 1331, 1342 (Fed. Cir. 2021). In light of our claim construction, we determine that Appellant’s Specification must enable the administration of a therapeutic dose of a blocking antibody that binds human CD49e and reduces the activity of CD49e+ myeloid cells in the CNS of a patient and that results in stabilizing or reducing clinical symptoms of ALS. The key enablement questions are whether a person of ordinary skill in the art was taught by Appellant’s Specification or would be able to determine, without undue experimentation, as of May 30, 2017, (1) the amount of CD49e antibody, if any, that would reduce the activity of CD49e+ myeloid cells in the CNS in a patient that has ALS, and (2) the effective dose of such an antibody that would be capable of stabilizing or reducing the clinical symptoms of ALS. We address the Wands factors with the foregoing in mind, as well as the fact that it is the Specification, when filed, that must enable one skilled in the particular art to Appeal 2021-002851 Application 15/993,172 16 use the invention without undue experimentation. See Idenix Pharms. LLC v. Gilead Sciences, Inc., 941 F.3d 1149, 1156 (Fed. Cir. 2019). The Examiner and Appellant dispute whether there is a reasonable correlation between the efficacy of a therapeutic protocol in the treatment of ALS in the SOD1 mouse model and in a human subject such that a therapeutic protocol in the treatment of ALS in a SOD1 mouse would provide enabling disclosure of a therapeutic method for humans as is claimed. We need not resolve this issue, however, to address the lack of enablement of Appellant’s Specification. That is because there is no therapeutic protocol for the treatment of ALS in a SOD1 mouse reported to have been carried out in the Specification. The Examiner determined that, irrespective of whether such a reasonable correlation exists, “the instant specification provides absolutely no evidence that the administration of an anti-CD49e antibody to either a human afflicted with ALS or a SOD1 mouse prevents or retards the progression of ALS.” (Final Action 7.) The Examiner noted, and Appellant does not dispute, that “the material presented in paragraphs [00191] and [00192] in Example 4 are proposals for experiments that had yet to be undertaken as of the filing of the instant application.” (Id.) The Examiner further noted that there is “no evidence that the skilled artisan in the field of neurobiology can reasonably predict the operability of a theoretical therapeutic protocol for the treatment of ALS based upon observations of changes in cell populations during the progression of ALS in an untreated Appeal 2021-002851 Application 15/993,172 17 SOD1 mouse.” (Id. at 8; Ans. 2012.) We agree and think that this is dispositive of the lack of enablement for the reasons that follow. SOD1 mouse model for mechanistic studies of ALS We conclude that there is sufficient evidence to establish that the SOD1 mouse model is an accepted model for ALS “enabling detailed mechanistic studies” of the disease. (Appeal Br. 5 (quoting Van Damme13 545).) Van Damme explains that “[r]odent models exist for genetic mutations that are most prevalent in ALS patients and are widely used to study disease mechanisms.” (Van Damme 544.) Van Damme notes that “important progress has been made in our understanding of the genetics and neuropathology of ALS, opening up new avenues for disease modelling research and for better characterizing the disease pathways that contribute to ALS.” (Id. at 545.) Van Damme explains that “[m]any different models are now being generated to investigate the recently identified ALS-associated genes” and that “[m]any fascinating disease mechanisms are emerging from models of ALS, such as impairments in nucleocytoplasmic transport, alterations in stress granule dynamics, transcriptional dysregulation, and non-neuronal cells acting as modulators of the disease.” (Id.) Van Damme states “[o]ur progress in the availability of multiple disease models for ALS research and in the knowledge about the 12 “In the instant case, the overwhelming evidence of record shows that there is no art-accepted correlation between a method of inhibiting the activity of CD49e myeloid cells in vitro, which Appellant has demonstrated possession of, and the ability of that method to stabilize or reduce the clinical symptoms of ALS in a human subject, which is what Appellant is claiming.” 13 Phillip Van Damme et al., Modelling amyotrophic lateral sclerosis: progress and possibilities, 10 Disease Models & Mechanisms 537-49 (2017). Appeal 2021-002851 Application 15/993,172 18 biology of the disease offers hope that robust therapeutic targets will be identified in the near future.” (Id.) Dr. Brown testifies that he has used the SOD1 mouse model to study “gene defects that elucidate how ALS causes neurons to die.” (Brown Decl. 1.) He also explains why the model is a “valuable preclinical model for studying treatments for human ALS.” (Id. at 2.) Dr. Brown also notes that ALS mice were used in the development of edaravone, a recently approved drug for use in ALS. (Id. at 2-3.) According to Dr. Brown, the anti- inflammatory properties of this drug “were first discerned in animal models, including trials in ALS mice.” (Id. at 3.) Dr. Appel testifies that “the mSOD1 transgenic mouse has been critical for identifying neuroinflammation as a meaningful therapeutic target in” his own studies. (Appel Dec. 2.) He explains that, using the model, his team “documented that neuroinflammation characterized by enhanced pro- inflammatory macrophages, microglia, and T lymphocytes was associated with rapid disease progression.” (Id.) We conclude that the foregoing establishes the SOD1 mouse model is an accepted model for ALS for diagnostic purposes of the disease. That, however, does not end the inquiry, because as noted above, Appellant’s claim is directed to a therapeutic method. The Therapeutic Method Claimed Is Not Enabled 1. Wands factors (4) the nature of the invention, (5) the state of the prior art, and (7) the predictability or unpredictability of the art There can be no dispute that ALS is a complex disease and finding treatments therefore has been difficult. Dr. Block states that ALS is a Appeal 2021-002851 Application 15/993,172 19 “complex and intractable disease[]” (Block Decl. 2.) Dr. Brown states that ALS has diverse pathophysiology. (Brown Decl. 2.) There is no dispute that a number of compounds to treat ALS have been tested in the prior art as a treatment using the SOD1 mouse model to treat the mouse and found effective in that model, but failed to show efficacy in humans. (See, e.g., Ans 4 (citing DiBernardo 1142); see also Brown Decl. 3, Final Action 7 (citing seven publications demonstrating positive results in animal models of neurodegenerative disease such as ALS and MS “more often than not fail to place in the hands of the neurobiologist an operable therapeutic protocol for the treatment of the disease being modeled.”).) Van Damme acknowledges that there have been “unsuccessful translation of findings from model organisms to patients [which] can be accounted for both by factors related to the model systems and factors related to the trial design in patients.” (Van Damme 545.) Several Declarants posit, with respect to ALS studies, that there were design flaws in the mouse testing such as too few animals being tested and thus were not appropriate to move to human trials (Brown Decl. 3, Appel Decl. 3). As for the ineffective translation from animal model to human treatment of compounds useful to treat ALS, whether the animal model used to test the treatment was flawed or the number of animals were too few, the evidence we discuss below establishes that one of ordinary skill in the art would not find Appellant’s disclosure - which does not even include evidence of testing a compound as a treatment in the SOD1 model of ALS - to enable the therapeutic method claimed. Appeal 2021-002851 Application 15/993,172 20 Dr. Appel’s use of the SOD1 mouse model and predicting therapeutic efficacy in ALS Dr. Appel opines that “studies of therapeutic efficacy in the mSOD1 mouse model of ALS are of considerable value in predicting therapeutic benefit in human ALS.” (Appel Decl. 2.) His studies leading to the clinical evaluation of regulatory T lymphocytes (Tregs) supports that. However, we note that Dr. Appel does not testify that the efficacy of Tregs to treat ALS in humans was reasonably predictable based simply on the diagnostic studies performed in SOD1 mice, in which it was observed that neuroinflammation characterized by enhanced pro-inflammatory macrophages, microglia, and T lymphocytes, was associated with rapid disease progression in the diagnostic model. Dr. Appel’s team notes that many steps were undertaken after the diagnostic use of the SOD1 model in his studies that determined efficacy of Treg. After the studies in SOD1 mice that characterized the cells that were enhanced in neuroinflammation in ALS, Dr. Appel’s team then studied the effect of eliminating T cells in these mice finding that “death was produced by the activated pro-inflammatory myeloid cells with activation dictated by the genetically-mediated removal of suppressive regulatory T lymphocytes (Tregs).” (Appel Decl. 2.) Next, his team tested Tregs in the modified SOD1 mice with eliminated T cells to determine if there was a clinical benefit. (Id.) There was: “survival was extended almost 100%.” (Id.) Next, the team “examined human ALS” to see if there was a similar phenotype as in the mouse model, which they did find. (Id.) After gaining regulatory approval, they studied efficacy of Tregs in a small number of ALS patients and found the Tregs were able to restore suppression of inflammatory T cells and macrohpages/microglia. (Id.) Appeal 2021-002851 Application 15/993,172 21 Dr. Appel does not state where along the line in the successive testing that he believes one of ordinary skill in the art would have reasonably believed Tregs would have reduced or stabilized clinical symptoms of ALS without undue experimentation. However, his testimony certainly suggests that studies of therapeutic efficacy in the SOD1 mouse model is minimally necessary. As we will discuss below, the testimony of Dr. Steinman, one of the named inventors, suggests the same. 2. Wands factor (3) the presence or absence of working examples SOD1 mouse model evidence in Appellant’s Specification The only experimental evidence in the Specification related to ALS, as the Examiner found (Final Action 4, 5), is characterization of CD49e expression by microglia in mSOD1 mice. (Spec. Example 3.) Appellant cannot and, in fact, does not dispute the foregoing. Appellant relies on the Declaration by Dr. Steinman as providing “supporting evidence for the activity of the antibody [to CD49e] in the treatment of an animal model for ALS.” (Appeal Br. 5.) Dr. Steinman states in his declaration: It is my position that our data, obtained with the rodent model for disease, contains sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue experimentation. I will first review and interpret the data in the specification; and provide additional supporting evidence for efficacy of our method; and will conclude with an overview of the animal model used and why it is the best model for methods such as ours, that address neuroinflammation in ALS patients. (Steinman Declaration 1 (emphasis added).) Appeal 2021-002851 Application 15/993,172 22 The data that Dr. Steinman reviews and interprets from the Specification is that of Example 3. As to that data, Dr. Steinman indicates that it demonstrates that (1) “the expression level of CD49e is increased at the disease end stage compare[d] to the onset of the disease,” in mice over- expressing human mutant dismutase 1, (2) a certain cell population “is increased significantly at the end stage of disease,” and (3) “frequency of the cells expressing TNFα, a major inflammatory cytokine, is increased in disease end-stage in mSOD1 mice.” (Steinman Declaration 2-3.) Noticeably absent from his review and interpretation of the Example 3 data is anything concerning a conclusion regarding the predictability of the use of an antibody to CD49e to ameliorate ALS based only on this data. In his Declaration, Dr. Steinman also describes SOD1 animal testing that is NOT present in the Specification. (Steinman Declaration 3-5.) Although Dr. Steinman indicates that this experiment is “further” validation “that an anti-α5 integrin will affect the course of ALS disease,” we conclude that it is not further validation at all, but the only evidence to support a conclusion that an antibody within the scope of the claim has some effect at reducing clinical symptoms associated with ALS. This is the only testing described by Dr. Steinman as a treatment. In the treatment testing method described by Dr. Steinman, some mSOD1 mice14 were administered anti-CD49e, while others were provided 14 10 mice were treated with anti-CD49e antibody and 10 were treated with isotype control antibody, while 5 received no treatment. (See Steinman Decl. 4.) We note that Dr. Appel indicates that too few animals being tested was a problem in previous studies of compounds tested for therapeutic use in mouse ALS experiments, which compounds did not prove clinically effective. (Appel Decl. 3.) Dr. Appel does not state how many mice is too Appeal 2021-002851 Application 15/993,172 23 with an isotype control, and a few mice received no treatment. (Steinman Decl. 5.) The mice were assessed daily to determine clinical signs of decline in motor function, paralysis, and survival. (Id.) The reported study results were that “[a]t the age of 175 days, 40% of the mice that received [the anti- CD49e antibody] survived, while 100% of the mice that received the isotype control and no treatment were dead.” (Id. at 4.) The Steinman Declaration concludes that, “[b]ased on [the cited] evidence, treating individuals with a blocking antibody to integrin α5 is reasonably expected to stabilize or reduce [disease].” (Id.) As we noted above, Dr. Steinman states It is my position that our data, obtained with the rodent model for disease, contains sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue experimentation. (Steinman Decl. 1.) The data that he discusses includes the administration of an anti-CD49e in the SOD1 mouse model to assess whether there was a benefit in those mice regarding motor function, paralysis, and survival. In short, Dr. Steinman’s declaration makes clear that the therapeutic data, which is not part of Appellant’s Specification, is part of the data that he considers necessary to provide reasonable predictability of treatment with a blocking antibody to CD49e to enable the claimed invention without undue experimentation. “‘It is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to few, but we note that subjecting 10 mice to treatment with the compound does not seem to be a large treatment cohort. Appeal 2021-002851 Application 15/993,172 24 constitute adequate enablement.’ Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997).” Idenix, 941 F.3d at 1159. Dr. Block’s testimony does not conflict with our conclusion that one of ordinary skill in the art would have needed to have the results of testing of an anti-CD49e in the SOD1 mouse, at a minimum, to consider the claimed therapeutic method to have been enabled. Dr. Block states that he has “reviewed the experimental work that underlies the above-captioned patent application.” (Block Decl. 2.) He states that “data from preclinical animal models is required to establish a useful mechanism of therapeutic action and to lay the groundwork for future clinical trials.” (Block Decl. 2.) He opines that the evidence obtained by Dr. Steinman in an animal model is appropriate for moving forward with further development of a human therapy. The underlying scientific rationale developed from the animal model reasonably correlates with what is known about neuroinflammation in human ALS, and with approaches to treatment of the inflammatory response in the human disease. (Block Decl. 3.) Notably, Dr. Block does not state that he has only reviewed the experimental work set forth in the Specification. See In re Wright, 999 F.2d 1557, 1563 (Fed. Cir. 1993) (noting that declaration evidence failed to support enablement because the declarants did not even indicate in their affidavits that they reviewed the Specification). We note that Dr. Block’s testimony refers to “findings” by Dr. Steinman “that a blocking antibody that specifically binds to human integrin α5 reduces the activity of CD49e+ myeloid cells in the central nervous system.” (Id.) Dr. Block does not refer to where in the Specification such findings are reported. And, as discussed above, Dr. Steinman himself relies on evidence that is not in the Appeal 2021-002851 Application 15/993,172 25 Specification that involves using the SOD1 mouse model to test a specific compound for therapeutic benefit in that regard. Thus, it is not clear to what animal model evidence in the Specification Dr. Block refers in concluding that it is appropriate to move forward with further development of a human therapy. In any event, Dr. Block’s belief, resulting from an unidentified animal model test that he has reviewed, that it “is appropriate to move forward with further development of a human therapy” and his statement that an unidentified mouse model used by Dr. Steinman is “useful in developing therapies that block neuroinflammation” does not speak to whether the Specification enables the therapeutic method claimed. It only addresses whether one of skill in the art in the research and development of therapeutics for ALS would be prompted to move forward in the drug development process with additional tests based on the animal model results. 3. Wands factors (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, and (6) the relative skill of those in the art, and (8) the breadth of the claims. We agree with Appellant that the relevant level of skill in the art is high. (Appeal Br. 7.) Appellant asserts the breadth of the claim “is not undue because the claim[] specifically recite[s] the use of an antibody that has a demonstrated desired activity on a targeted myeloid cell population. (Id.) Whether the claim is “undue” depends upon what Appellant’s Specification enables with respect to what is claimed. The claim is to a therapeutic method which must be achieved by an antibody having the particular function of specific binding to reduce the activity of CD49e+ myeloid cells and stabilize or reduce the Appeal 2021-002851 Application 15/993,172 26 clinical symptoms of ALS. We have discussed what has been “demonstrated” in the Specification above with respect to ALS, and it is NOT testing a compound in the SOD1 model to determine amelioration of disease. It is only the diagnostic use of the SOD1 model in determining what the microglia populations looks like as ALS progresses. The Specification does not identify a particular antibody that binds to human integrin α5 and reduces the activity of CD49e+ myeloid cells in an ALS model of disease. It identifies that CD49e expression in microglia populations at disease end-stage in SOD1 mice is increased compared to disease onset. (Spec. ¶ 187.) It identifies 5H10-27 (MFR5) as an antibody that binds to human integrin α5 (Spec. ¶ 183) and that it delayed the onset of EAE disease, the mouse model of MS. (Spec. ¶ 149.) However, as the Examiner noted, and Appellant does not dispute, EAE “is not considered to be an art-accepted model of ALS at all.” (Ans. 12.) There is no evidence that a person of ordinary skill in the art at the time of the filing of the application would have reasonably believed that an antibody that specifically binds to human integrin α5, such as MFR5, would reduce the activity of CD49e+ myeloid cells in the central nervous system in a patient with ALS, or would be effective in stabilizing or reducing clinical symptoms of ALS, just because it was found to delay the onset of disease in a different disease model that is not an accepted model for ALS. As we noted above, Van Damme acknowledges that there have been “unsuccessful translation of findings from model organisms to patients [which] can be accounted for both by factors related to the model systems and factors related to the trial design in patients.” (Van Damme at 545.) Van Damme thus supports that the studies in the EAE mouse model with MFR5 Appeal 2021-002851 Application 15/993,172 27 are not reasonable to rely on to predict therapeutic results in a different model system. We find further that Dr. Appel’s testimony supports a conclusion that the mSOD characterization study of microglia in Appellant’s Specification, while no doubt useful in determining potential therapeutic targets, is not sufficient to establish enablement for the therapeutic method claimed. Dr. Appel and Dr. Steinman’s testimony indicate that at least a test of the compound in a rodent model representative of ALS to assess its benefit in ameliorating ALS is necessary. Appellant’s Specification does not provide such testing. Indeed, there is very little guidance in the Specification regarding the claimed method of treating ALS. Paragraph 64 states: “Although not traditionally classified as an inflammatory disease, ALS has been found to have increased numbers of CD49e macrophages, and may be treated by the methods described herein.” But as we just noted, no methods are described as having been carried out for ALS. Paragraphs 191 and 192 of the Specification, as the Examiner noted, pose a hypothetical protocol to test whether there is any observed treatment effect with 100 micrograms of anti-CD49e antibody. Paragraph 190 simply concludes from the diagnostic data reported in Example 3 that inhibition of CD49e is a therapeutic target for ALS disease. “It is not enough to identify a ‘target’ to be the subject of future testing.” Idenix, 941 F.3d at 1161. As noted above, even Dr. Steinman does not conclude the diagnostic data from Example 3 is sufficient to enable the claimed method without undue experimentation. He indicates that the actual Appeal 2021-002851 Application 15/993,172 28 testing of the compound and the observation that there was a therapeutic response is needed. Paragraph 102 of the Specification just generally identifies a broad range of “effective dose of an anti-α5 agent of the invention [that can be] administered alone, or combined with additional active agents for the treatment of a condition as listed above.” There is nothing else in the Specification for one of ordinary skill in the art to determine what dose and agent would be able to treat ALS in humans in the manner required by the claims. As noted, Dr. Steinman’s Declaration refers to an experiment that may shed light on that, but that evidence is not part of the Specification, and it is not even clear that the experiment was carried out by the time of the effective filing date of the application. While a post-filing declaration may be used to show the accuracy of a statement in the specification, it cannot “render an insufficient disclosure enabling.” In re Brana, 51 F.3d 1560, 1567 n.19 (Fed. Cir. 1995). We conclude that Appellant’s Specification merely proposes an unproved hypothesis consisting of little more than a respectable guess as to the likelihood of its success. Rasmusson, 413 F.3d at 1325. It is “a starting point, a direction for further research,” into whether an antibody to human α5 can be found that will reduce the activity of CD49e+ myeloid cells in ALS patients and that such reduction in activity will stabilize or reduce the clinical symptoms of ALS. Genentech, 108 F.3d at 1366. Such disclosure does not satisfy enablement. Id. (“Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. . . . Tossing out the mere germ of an idea does not constitute enabling disclosure.”). Appeal 2021-002851 Application 15/993,172 29 We conclude, like the Examiner, that with respect to the claimed therapeutic method, Appellant’s disclosure is simply a “general suggestion” that may or may not be workable. (Final Action 6-7; Ans. 11-12.) Thus, we affirm the Examiner’s rejection of claim 1 as not being enabled. Where “claims are not separately argued, they all stand or fall together.” In re Kaslow, 707 F.2d 1366, 1376 (Fed. Cir. 1983); 37 C.F.R. § 41.37(c)(1)(iv). Appellant states that grouping the claims into four different groups “[f]or the rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA),” is appropriate. (Appeal Br. 3.) However, in presenting its argument to contest the Examiner’s rejections, Appellant does not provide separate argument for the various claim groupings. Thus, we find Appellant has not argued claims 2, 8-10, and 14-24 separately. Accordingly they fall with claim 1. II. Lack of Written Description The written description requirement is separate from enablement. Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1347 (Fed. Cir. 2010) (en banc) (upholding a written description requirement separate from enablement based in part on stare decisis ). To satisfy the written description requirement, the Specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63 (Fed. Cir. 1991). Appellant must demonstrate such possession “by disclosure in the specification of the Appeal 2021-002851 Application 15/993,172 30 patent.” Carnegie Mellon University v. Hoffman-La Roche, 541 F.3d 1115, 1122 (Fed. Cir. 2008). Specifically, to have “possession,” the Specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art and show that the inventor actually invented the claimed invention. Id.; Ariad, 598 F.3d at 1351. “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011). The Examiner stated that To demonstrate possession of a method of treatment one must provide substantially more than the description of a compound having an in vitro activity, in combination with a hypothesis that the administration of a compound having that activity to an individual suffering from a particular disease or disorder might produce a beneficial effect. What is required is an established nexus between the administration of such a compound to an individual and a beneficial result consequent thereto. (Ans. 13.) The Examiner states the nexus can be established for the claimed therapeutic invention by demonstrating clinical efficacy of the claimed method in the treatment of a particular disease or disorder, demonstrating efficacy of that method in the treatment of an art accepted animal model of a disease or disorder wherein that model is known to be reasonably predictive of the efficacy of a treatment protocol in the treatment of that disease or disorder, or providing evidence of an in vitro activity for the recited therapeutic compound, or class of compounds, in combination with a showing that other compounds possessing that activity (mode of action) have been shown to have clinical efficacy in the treatment of the recited disease or disorder. (Id.) The Examiner explains that the application provides none of these. Appeal 2021-002851 Application 15/993,172 31 Appellant has not separately addressed the Examiner’s rejection of claims 1, 2, 8-10, and 14-24 as failing to comply with the written description requirement (Final Action 11). As noted in the enablement discussion, Appellant’s Specification does not provide a demonstration of evidence of efficacy of the method in the treatment of an art accepted animal model of the disease. Appellant’s brief addressing enablement does not assert that an example of clinical efficacy is demonstrated, or that a class of compounds possessing the activity of the antibody recited in the claim has been shown to have clinical efficacy in the treatment in ALS. We conclude Appellant has waived substantive argument regarding the Examiner’s written description rejection and we, therefore, summarily affirm that rejection. Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008) (“When the appellant fails to contest a ground of rejection to the Board, . . . the Board may treat any argument with respect to that ground of rejection as waived.”). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2, 8-10, 14-24 112(a) Enablement 1, 2, 8-10, 14-24 1, 2, 8-10, 14-24 112(a) Written Description 1, 2, 8-10, 14-24 Overall Outcome 1, 2, 8-10, 14-24 Appeal 2021-002851 Application 15/993,172 32 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