Regenesance B.V.

Patent Trials and Appeals Board

Feb 16, 2022

2022000511 (P.T.A.B. Feb. 16, 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. 15/673,167 08/09/2017 Frank BAAS RGJ-002USCN2 5760 959 7590 02/16/2022 NELSON MULLINS RILEY & SCARBOROUGH LLP ONE FINANCIAL CENTER SUITE 3500 BOSTON, MA 02111 EXAMINER HAYES, ROBERT CLINTON ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 02/16/2022 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): ipboston.docketing@nelsonmullins.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte FRANK BAAS and VALERIA RAMAGLIA __________ Appeal 2022-000511 Application 15/673,167 Technology Center 1600 __________ Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and TAWEN CHANG, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve. The Examiner rejected the claims under 35 U.S.C. § 112(a) as failing to comply with the written description and scope of enablement requirements. 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 Regenesance B.V. (see Appeal Br. 2). Appeal 2022-000511 Application 15/673,167 2 Statement of the Case Background “Axonal degeneration is the main cause of disability both in hereditary and in acquired demyelinating neuropathies. While most current therapeutic research aims at restoring myelination, the present inventors focus on the consequence of demyelination: secondary axonal degeneration” (Spec. 3:13-16). “The present invention is based on the surprising finding that axonal regeneration is enhanced in rats that arc deficient in the complement C6 factor. This surprising finding opens new ways to promote axonal regeneration by manipulation of the complement system and/or macrophage activation” (Spec. 3:24-27). The Claims Claims 15-20, 22-25, and 27 are on appeal. Independent claim 15 is representative and reads as follows: 15. A method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is an antisense oligonucleotide that binds to the mRNA sequence of human CS or C6 of the complement system. The Issues A. The Examiner rejected claims 15-20, 22-25, and 27 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement (Final Act. 2-5). B. The Examiner rejected claims 15-20, 22-25, and 27 under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement (Final Act. 5- 11). Appeal 2022-000511 Application 15/673,167 3 A. 35 U.S.C. § 112(a), written description The Examiner finds that, while the Specification may suggest the “use of undefined antisense oligonucleotides,” “not a single antisense oligonucleotide is described that binds any known gene sequence, nor is any specific sequence defined that can be constructed that reasonably treats any specific neurodegenerative disorder requiring axonal regeneration” (Final Act. 4). The Examiner finds “one skilled in the art cannot reasonably visualize or predict what critical nucleotide residues would structurally characterize the genus of antisense oligonucleotides required to successfully practice these broadly claimed methods” (id.). Appellant contends, based on Capon v. Eschhar, 418 F.3d 1349 (Fed. Cir. 2005), that inhibitors of MAC formation include anti-sense oligonucleotides, specifically, anti-sense oligonucleotides that bind to (i.e., are structurally complementary to) the mRNA sequence of human CS or C6 (see e.g., page 9, lines 4-13, of the present specification). Moreover, the gene sequences of human CS and C6 were well known at the relevant filing date of the present application. (Appeal Br. 5). Appellant asserts that “techniques for generating inhibitory antisense molecules also were well known in the art at the relevant filing date” and that “during the past 30 years (i.e., since the above noted publication) and prior to the filing of the present application, the level of skill in the art for making and using antisense oligos has continued to mature” (id. at 5-6). Appellant contends that the functional “recovery demonstrated in Examples 3 and 4 [of the Specification] provides evidence that complement inhibitors, such as anti-[sense] CS and anti-sense C6 [oligos], can be used to inhibit MAC formation and promote axonal Appeal 2022-000511 Application 15/673,167 4 regeneration, as well as treat neurodegenerative diseases and/or damaged nerves, as claimed” (id. at 6). We find the Examiner has the better position. In Amgen, the Court explained that: An adequate written description must contain enough information about the actual makeup of the claimed products - “a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017). Applying the Amgen written description analysis to these facts, we agree with the Examiner that the Specification lacks any definition, structure, chemical name, physical or other properties of any specific antisense oligonucleotide that treats any neurodegenerative disease, diabetes, or cardiovascular disease. We appreciate that the sequences of C5 and C6 were known in the prior art, consistent with Capon v. Eshhar, 418 F.3d 1349 (2005). However, Capon dealt with a claim where “their chimeric genes are produced by selecting and combining known heavy- and light-chain immune-related DNA segments, using known DNA-linking procedures.” Id. at 1355. Unlike Capon, there are many requirements of the instant claims that are neither described by the Specification or by the prior art. Appellant does not provide meaningful guidance as to which antisense oligonucleotides designed based on the C5 and C6 sequences, if any, will bind the identified targets, which antisense oligonucleotides will have therapeutic effect to treat Appeal 2022-000511 Application 15/673,167 5 any particular neurodegenerative disease, diabetes, or cardiovascular disease, and how any of these antisense oligonucleotides may be delivered to proper location in the body, whether neural tissue, cardiovascular tissue, pancreatic tissue, or some other location. Thus, neither the specific active antisense oligonucleotides nor the procedures for treating patients for the scope of the claims is described. The written description concern is consistent with Juno Therapeutics, Inc., v. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021), where the Court explained “this patent provides nothing to indicate that the inventors possessed the full scope of the genus that they chose to claim.” As in Juno, Appellant provides no evidence that as of the 2007 filing date, it would have been routine to design therapeutically effective antisense oligonucleotides to specific genes that could then be delivered to the proper location in the human body for treatment of any of the broad class of diseases encompassed by the claims. To be clear, we are not disputing that given the 1700 nucleotide length sequence disclosed in Lundwall2 (see Lundwall 2110), an ordinary artisan could not select short 18 to 24-mer antisense oligonucleotides, and even that some of these randomly selected antisense oligonucleotides might have some ability to interfere with expression of C5 in an in vitro expression system. But Appellant’s claims are not drawn to in vitro inhibition, and not even to some degree of in vivo inhibition but rather to “a therapeutically effective amount.” The Specification defines “therapeutic amount” as “that 2 Lundwall et al., Isolation and Sequence Analysis of a cDNA Clone Encoding the Fifth Complement Component, 260 J. BIOL. CHEM. 2108- 12 (1985) Appeal 2022-000511 Application 15/673,167 6 amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective treatment of the injury or disorder” (Spec. 5:5-7). Appellant has provided no evidence properly on the record of even a single antisense oligonucleotide disclosed in the Specification that functions to treat a single disease in a single patient at the correct bodily locus. Indeed, the sole disclosure of antisense oligonucleotides in the Specification provides no parameters, delivery methods, diseases that would be treatable, or other therapeutic information (see Spec. 13:3-9). And the Baas Declaration3, refused entry by the Examiner and therefore not properly before us4 (see Final Act. 7) was dated more than 9 years after the priority date. Thus, the Baas Declaration does not establish what was described as of 2007. And the Baas Declaration, like the Specification, does not provide the sequence of any antisense oligonucleotide tested or used for treatment, but simply refers to them by name, and does not establish that these tested sequences were known prior to 2007. The Baas Declaration not only lacks any indication that it relied solely upon information available in 2007, but expressly relates that one of the models used was not developed until 2009 (see Baas Decl., App’x A at 3). The Baas Declaration provides no disclosure regarding how the antisense oligonucleotides used were selected, whether that selection methodology was available prior to the instant priority date of 2007, whether other antisense oligonucleotides that failed were excluded, and if some 3 Declaration of Dr. Frank Baas, dated Feb. 14, 2016. 4 We note that: “Review of an examiner’s refusal to enter an affidavit as untimely is by petition and not by appeal to the Patent Trial and Appeal Board.” MPEP § 715.09. Appeal 2022-000511 Application 15/673,167 7 failed, how many. We therefore conclude that this post-priority date Declaration, substantially deficient in disclosure, does not persuasively establish that the ordinary artisan, as of 2007, would have found selection of “therapeutically effective” antisense oligonucleotides to C5 and C6 as routine as combining known DNA segments in Capon. See In re American Academy of Science Tech Center, 367 F.3d 1359, 1370 (Fed. Cir. 2004) (“[T]he Board is entitled to give such weight to declarations as it deems appropriate.”) Therefore, we sustain the Examiner’s rejection of claim 15 as ineligible subject matter under § 112, first paragraph. As a result, we also sustain the rejection of claims 16-20, 22-25, and 27 under § 112, first paragraph. See 37 C.F.R. § 41.37(c)(1)(iv). B. 35 U.S.C. § 112(a), scope of enablement The Examiner finds it cannot be successfully extrapolated from the limited examples as described within the specification (in which not a single working example shows use of any antisense oligonucleotides) whether the skilled artisan has successfully practiced Applicant’s invention without requiring undue experimentation to first discover how to make and use Applicants’ invention, as currently claimed. (Final Act. 11). Appellant responds that, based on “the guidance in the specification, combined with the well-developed knowledge and skill in the art at the relevant filing date, one of ordinary skill clearly would be able to practice the presently claimed methods without undue experimentation” (Appeal Br. 10). Appeal 2022-000511 Application 15/673,167 8 The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner’s conclusion that the claims fail to comply with the enablement requirement? Findings of Fact Breadth of Claims 1. Claim 15 broadly encompasses inhibiting the formation of a membrane attack complex in any neurodegenerative disorder and any physical injury of a nerve using any antisense oligonucleotide that is capable of binding to any human C5 or C6 complement system sequence. 2. The Specification teaches physical injuries include spinal cord lesions as well as traumatic wounds to peripheral nerves, including injuries from collisions, motor vehicle accidents, gun wounds, fractures, dislocations, lacerations, or some other form of penetrating trauma. Peripheral nerves injured through trauma that may be treated include the digital, median, ulnar radial, facial, spinal accessory and brachial plexus nerves. (Spec. 5:26-31). 3. The Specification teaches that demyelinating diseases include e,g. Guillain-Barré syndrome . . . Similarly chronic inflammatory demyelinating polyneuropathy (CIDP), considered the chronic counterpart of GBS, may be treated with the methods and/or the medicaments of the invention. Multiple sclerosis (MS) is another demyelinating disease that may be treated with the methods and/or the medicaments of the invention. Further, neurodegenerative CNS and/or PNS disorders with a genetic component that may he treated with the methods and/or the medicaments of the invention include Amyotrophic Lateral Sclerosis (ALS, sometimes called Lou Gehrig’s disease), Appeal 2022-000511 Application 15/673,167 9 Charcot-Marie-Tooth disease (Hereditary Motor and Sensory Neuropathy, HMSN) and Huntington’s Disease (HD). (Spec. 6:16-30). Presence of Working Examples 4. There are no working examples using any antisense oligonucleotide, uses inhibitors that interact with C5 or C6 sequences or treats any of the specific diseases listed other than acute nerve trauma (see Spec. generally). 5. There are working examples in rats using a C1 inhibitors or soluble CR1 competitor, but these are not antisense oligonucleotides (see Spec. 21-37; Examples 2-5). Amount of Direction or Guidance Presented 6. The Specification mentions oligonucleotides in a single paragraph, reproduced below: Methods for producing nucleic acid inhibitors of complement such as anti-sense oligonucleotide, aptamer, miRNA, ribozyme, siRNA, are known to the skill person persé [sic]. Preferably such nucleic acid inhibitors comprise one or more modified nucleotides such as e.g. 2’-O substituted ribonucleotides, including alkyl and methoxy ethyl substitutions, peptide nucleic acid (PNA), locked nucleic acid (LNA) and morpholino antisense oligonucleotides and ethylene bridged nucleotides (ENA) and combinations thereof. (Spec. 13:3-9). State of the Prior Art and Unpredictability of the Art 7. Lundwall teaches “the complete nucleotide structure of this clone and the results obtained on comparison of the derived C5 protein Appeal 2022-000511 Application 15/673,167 10 sequence (438 amino acid residues)” (Lundwall 2108, col. 2). Haefliger5 teaches “we have analyzed the complete molecular structure of complement C6 as derived from the cDNA sequence” (Haefliger 18041, col. 2). 8. Jackowski teaches: It seems certain that CNS [central nervous system] oligodendrocytes and myelin, possibly also PNS [peripheral nervous system] myelin, possess membrane- or extracellular matrix-associated molecules that inhibit the successful regeneration of adult mammalian CNS and PNS axons. The lack of any significant regrowth of lesioned axons in CNS grey matter (where there is minimal myelin) or in myelin-deficient mutant mammals, together with an inability of regenerating dorsal root sensory axons to cross the DRTZ, highlights also the inhibitory role of reactive astrocytes and a relative lack of neurotrophic molecules as being other important factors for CNS regeneration failure. (Jackowski 311, col. 1). 9. Ramaglia,6 an inventor publication, teaches “inhibition with sCR1 up to 1 week post-injury is sufficient to speed up regeneration” and expresses the belief that “C-mediated events which occur during the first week of the degenerative process influence the subsequent nerve regeneration and recovery” (Ramaglia 308, col. 1). Ramaglia teaches “[d]elayed clearance of myelin debris in the C6−/− nerve or with sCR1 treatment does not appear to hamper regeneration” (Ramaglia 308, col. 2). 5 Haefliger et al., Complete primary structure and functional characterization of the sixth component of the human complement system: Identification of the C5b-binding domain in complement C6, 264 J. BIOL. CHEM. 18041-51 (1989). 6 Ramaglia et al., Complement inhibition accelerates regeneration in a model of peripheral nerve injury, 47 MOL. IMMUNOLOGY 302-9 (2009). Appeal 2022-000511 Application 15/673,167 11 Ramaglia teaches its “findings should encourage the testing of newly available anti-C therapeutics for inhibition of C activation after repair of peripheral nerve damage or transection” (Ramaglia 308, col. 2). 10. Sta7 follows up on Ramaglia’s teachings and uses “a model with only modest activation of the complement system. In this way we could study nerve de- and regeneration in an experimental setting that excluded confounding effects of high levels of complement activation, MAC deposition, in WT animals, while still sufficient damage was delivered to induce WD” (Sta 27, col. 1). Sta teaches that we found no differences in axonal outgrowth between WT animals and C6−/− animals following the 1.5 mm sciatic nerve crush injury. This indicates that the earlier regeneration of C6−/− nerves observed after the 2.0 mm injury is likely linked to the difference in MAC deposition between WT and C6−/− animals and not caused by an inherent difference between the two strains. (Sta 31, col. 1). Sta concludes “that the C6 status in PVG rats is not sufficient to alter axonal regrowth speed” (Sta 32, col. 1). 11. Tamm8 teaches that only a single antisense oligonucleotide was approved for any therapy, as of the filing date, specifically “for the treatment of CMV-induced retinitis in patients with AIDS” (Tamm 223, col. 1). Tamm teaches that an antisense oligonucleotide targeted towards cancer, oblimersen, failed in treatment of multiple myeloma (Tamm 227, col. 1) and 7 Sta et al., C6 deficiency does not alter intrinsic regeneration speed after peripheral nerve crush injury, 87 NEUROSCIENCE Res. 26-32 (2014). 8 Tamm et al., Antisense Therapy in Clinical Oncology, 33 MOLECULAR BIOTECHNOLOGY 221-38 (2006). Appeal 2022-000511 Application 15/673,167 12 “failed to receive an affirmative vote for approval by an advisory committee to the FDA because overall survival of the ITT population was not significantly prolonged and the improvements in time-to-progression were not deemed clinically significant” (Tamm 228, col. 1). Tamm reviews other antisense therapies for cancer and concludes generally that “the proof of clinical efficacy of AS ODN in the field of oncology is still missing” (Tamm 235, col. 1). Quantity of Experimentation 12. Tamm teaches that, after developing in vitro evidence in order to determine the efficacy of antisense oligonucleotides as therapy, FDA Phase I, II, and III trials at great expense and effort were required (see, e.g. Tamm 229 (“After safety of ISIS 5132 was demonstrated in these phase I trials, several phase II trials were initiated. There was no evidence of single agent activity of ISIS 5132 in pretreated patients with recurrent ovarian cancer.”)). Skill in the Art 13. The cited art, replete with papers from scientists with advanced degrees, suggests that the skill in the art is high (cf. FF 7-11). Principles of Law 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 predictability or Appeal 2022-000511 Application 15/673,167 13 unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Analysis “The requirement of enablement, stated in 35 U.S.C. § 112, enforces the essential ‘quid pro quo of the patent bargain’ by requiring a patentee to teach the public how ‘to practice the full scope of the claimed invention.’” Pacific Biosciences California, Inc. v. Oxford Nanopore Tech., Inc., 996 F.3d 1342, 1350 (Fed. Cir. 2021) (citing McRO, Inc. v. Bandai Namco Games America Inc., 959 F.3d 1091, 1096 (Fed. Cir. 2020). “[A] patentee chooses broad claim language at the peril of losing any claim that cannot be enabled across its full scope of coverage.” MagSil Corp. v. Hitachi Glob. Storage Techs., Inc., 687 F.3d 1377, 1381 (Fed. Cir. 2012) The Specification provides no guidance whatsoever on the use of antisense oligonucleotides to C5 or C6 (FF 6) for treatment of any of the enormous numbers of diseases recited (FF 2-3). The Specification has no working examples of such an antisense oligonucleotide (FF 4). The Specification provides no guidance on how to design a functional antisense oligonucleotide from the large number of possible compounds encompassed by claim 15 that has therapeutic effect. The Specification does not teach how to deliver a functional antisense oligonucleotide to the physical location in the body in order to obtain the required therapeutic effect. “[W]e h[o]ld that due to the large number of possible candidates within the scope of the claims and the specification’s corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the Appeal 2022-000511 Application 15/673,167 14 claimed functionality.” Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080, 1086 (Fed. Cir. 2021). And claim 15 requires more than the identification of antisense generally, it requires antisense with a therapeutic effect. “Without specific guidance on that point, the specification provides ‘only a starting point, a direction for further research.’” Idenix Pharm. LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1160 (Fed. Cir. 2019) (citing ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 941 (Fed. Cir. 2010)). Instead, at best, the Specification provides the germ of an idea, that an artisan might design an antisense oligonucleotide to C5 or C6 that might treat some disease. If the artisan, likely highly skilled (FF 13), takes up Appellant’s challenge, the artisan does have the known sequences of C5 and C6 (FF 7). But the artisan would not only have to contend with difficulties in neuronal regrowth due to “molecules that inhibit the successful regeneration of adult mammalian CNS and PNS axons” (FF 8), but also with Sta’s finding that the Ramaglia regrowth model (FF 9) showed “no differences in axonal outgrowth between WT animals and C6−/− animals following the 1.5 mm sciatic nerve crush injury” (FF 10). Sta “conclude[d] that the C6 status in PVG rats is not sufficient to alter axonal regrowth speed” (FF 10). Thus, the artisan would find that Sta teaches away from the use of C5 and C6 treatments, like antisense oligonucleotides, for treatment of diseases requiring neuronal regrowth. Tamm evidences that an immense quantity of work is necessary to even get these antisense oligonucleotides to the point of testing whether they function as therapeutic agents (FF 12). Tamm shows that treatment with any particular antisense oligonucleotide is unpredictable, as many (though not Appeal 2022-000511 Application 15/673,167 15 all) fail during clinical trials (FF 11). For example, Tamm teaches “the proof of clinical efficacy of AS ODN [antisense oligonucleotides] in the field of oncology is still missing” (FF 11). And Tamm’s human clinical trials occur after highly skilled artisans have already spent large amounts of time and effort in identifying which antisense oligonucleotides, if any, for a particular target are capable of resulting in any inhibitory effect in vitro and demonstrating which of these function in animal models. While we recognize that human trials are not necessary to establish enablement, the current Specification and claims do not even provide guidance on how to design antisense oligonucleotides to C5 and C6, much less provide the artisan with any guidance on functional antisense oligonucleotides that might be used for in vitro or animal testing. Appellant contends that “the studies described in Example 3 showed that rats treated with sCR1 (an inhibitor of the complement pathway) recovered sensory function faster than control rats, and that sCR1 strongly inhibited influx and activation of macrophages (see also Figures 6 and 7)” (Appeal Br. 8). We recognize that Appellant has a working example of a complement inhibitor in the Specification (FF 5)9 but the example is not drawn to an 9 We note, as discussed in the written description analysis above, that the Examiner found the Baas Declaration is not properly of record here. And to the extent that the Baas Declaration has described antisense oligonucleotides that show some limited therapeutic effects in animal models (see, e.g., Baas Decl. App’x A), there is no evidence or indication that the antisense oligonucleotides were designed based on information known by the priority date of the instant application and therefore addresses enablement at the time of invention. Appeal 2022-000511 Application 15/673,167 16 antisense oligonucleotide. That a different treatment modality functions provides limited evidence supporting the full scope of enablement of any antisense oligonucleotide of any design that binds to C5 or C6 for treatment of any of the large list of diseases recited (FF 2-3) by any delivery method whatsoever. “Where, as here, working examples are present but are “very narrow, despite the wide breadth of the claims at issue,” this factor weighs against enablement.” Idenix, 941 F.3d at 1161. Appellant contends: This data more than reasonably correlates with antisense inhibitors of C5 and C6, and is further expanded upon in post filing publications (i.e., Ramaglia et al. (2007) J. Neurosci. 25:7663-7672 and Ramaglia et al., (2009) Mol. Immnol. 47:302-309, both enclosed with Appellant’s IDS submitted on December 8, 2017) and provides clear evidence that complement inhibitors, such as the claimed C5 or C6 antisense oligonucleotides, are effective in promoting functional recovery of damaged or degenerating nerves in a patient. (Appeal Br. 9). We have considered the Ramaglia references but note that Sta follows up on Ramaglia’s teachings and “found no differences in axonal outgrowth between WT animals and C6−/− animals following the 1.5 mm sciatic nerve crush injury” (FF 10). Thus, as we balance these teachings, we find that Sta undermines the factual predicate underlying Ramaglia’s disclosure. Sta suggests that the absence or inhibition of C6 may not necessarily permit neuronal growth after nerve damage such as a crush injury (FF 10). Thus, the overall art does not support Appellant’s reliance on Ramaglia. Appellant contends the Examiner relies on two publications from 1995. published more than 10 years before the filing date of the present Appeal 2022-000511 Application 15/673,167 17 application, in asserting that there was unpredictability of in vivo gene therapy/gene expression manipulation (i.e., “Report on Recommendations of the Panel to Assess the NIH investment in Research on Gene Therapy; and Still and Szoka (1995)). However, these references do not reflect advancements in antisense technology up to the relevant filing date of the present application (i.e. October 10, 2007). (Appeal Br. 9). While we do not rely on these references of the Examiner, we note that Appellant provides no persuasive evidence, as opposed to attorney argument, that suggests that design of antisense oligonucleotides was a solved issue in 2007, that therapeutic effect of such selected antisense oligonucleotides was routine in the art in 2007, or that proper delivery of such antisense oligonucleotides for therapeutic effect required minimal experimentation in 2007. None of the references cited by Appellants asserts that antisense oligonucleotide therapy was routine in 2007. See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). Thus, we agree with the Examiner that when the Wands factors are considered as a whole, the scope of these claims require undue experimentation for the public to practice and does not provide a disclosure that satisfies the quid pro quo of the patent bargain. Appeal 2022-000511 Application 15/673,167 18 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 15-20, 22-25, 27 112(a) Written Description 15-20, 22- 25, 27 15-20, 22-25, 27 112(a) Enablement 15-20, 22- 25, 27 Overall Outcome 15-20, 22- 25, 27 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED