DETAILED ACTION
This Action is in response to the communication filed on 06/09/2026.
Claims 1, 15-17, 20-26, 28-29, 31-33 are pending.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 15-17, 20-26, 28-29, 31-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to a method of treating schizophrenia or bipolar type II disorder by administering any of a number of specific therapeutic agents for treating schizophrenia or bipolar disorder. However, the claimed method is still not enabled because the evidence of record indicates that it would be unpredictable if the claimed method could be practiced with a reasonable expectation of success and in view of the lack of working examples demonstrating that the claimed method could be successfully practiced without an unreasonable amount of additional experimentation.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant' s claims are not enabled.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that it encompasses a method of treating schizophrenia or bipolar type II disorder by administering any of a number of specific therapeutic agents and further decreasing expression and/or activity of STAB1 polypeptide in a cell in the subject by administering a STAB1 inhibitor that is an inhibitory nucleic acid comprising an antisense nucleic acid molecule, a siRNA, or a shRNA that hynridizes to a STAB1 nucleic acid molecule. A skilled artisan would not be able to practice (i.e., use) the method with a reasonable expectation of success based on the evidence of record.
The amount of direction provided by the inventor and the level of predictability in the art:
With respect to the pending claims, the specification teaches the general structure and function of STAB1 siRNA inhibitors and gapmer antisense inhibitors, The specification discloses a broad range of possible administration routes on page 27 and possible vectors on page 16. Additionally, the specification notes on page 3 that, “STAB1 is primarily expressed on sinusoidal endothelial cells of liver, spleen, and lymph node”, and “in the brain STAB1 is selectively expressed in microglia cells”, but does not identify the specific target organ(s) or cell type for a STAB1 inhibitor that would lead to treatment of schizophrenia or bipolar disorder type II.
The art at the time of filing provided enabling guidance for the delivery of a small number of nucleic acid molecule-based human disease treatments, of which only one was delivered to the central nervous system, and none were for treatment of any psychiatric disorder including schizophrenia or bipolar disorder type II (Roberts et al., Nature Reviews Drug Discovery, 2020; of record). Further, “despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation” (Roberts et al., page 673) and “systemic delivery to the central nervous system (CNS) presents an additional obstacle, as oligonucleotide-based therapeutics are generally not able to traverse the blood–brain barrier (BBB)” (Roberts et al., page 677). “CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood” (Pardridge, Front. Aging Neurosci., 2020; of record). “In 2019, there is not a single recombinant protein that is FDA approved for brain disease, wherein that drug must cross the BBB. The main factor limiting CNS drug development is the BBB, as 98% of all small molecules do not cross the BBB, and ~100% of large molecule drugs do not cross the BBB. Multiple clinical trials of CNS disease have been attempted with recombinant proteins over the last 25 years, and all such clinical trials have failed” (Pardridge, page 20).
The art at the time of filing provided enabling guidance for the application of genomics to inform treatment for a limited number of Mendelian diseases (genetic disorders caused by mutations in a single gene), such as cystic fibrosis and muscular dystrophy, and specific cancers, or to inform dosage for well described drugs, such as warfarin (Ashley, Nature Reviews Genetics, 2016, of record). Ashley discusses major challenges in reliably using genomics in drug discovery and development, stating, “the concept of causality is fundamental and recurrent in clini-cal genetics, as science has provided an abundance of association evidence. Indeed, discovery genetics has identified robust statistical associations between diseases and genetic variants but for a variant to be use-ful as a diagnostic test or therapeutic target, it is crucial to demonstrate a causal link. Achieving confidence in the determination of causality between a gene or variant and a disease is a complex task that requires various types of supportive data” (Ashley, page 519). MacArthur et al. describe standards for the robust differentiation between disease-causing genetic variants and other variants present in the human genome, which includes experimental validation of the “predicted damaging impact of candidate variants using assays of patient-derived tissue or well-established cell or animal models of gene function” (MacArthur et al., Nature, 2014; Box2, page 471 and Table 1, page 472; of record). Additionally, Dugger, Platt, and Goldstein comment on the unreliability of “the use of genomics to identify gene variants that point directly to new targets for treating common conditions”, stating, “with the nota-ble exceptions of drugs targeting sclerostin (encoded by SOST) and the α-subunit of the voltage-gated sodium channel protein type 9 Nav1.7 (encoded by SCN9A) (BOX 1), early attempts to utilize this approach have rarely resulted in new drugs being discovered and developed. Hence, it seems likely that such pointers to generally use-ful medicines, regardless of underlying causes of disease in individual patients, may be fairly rare” (Dugger, Platt, and Goldstein. Nature Reviews Drug Discovery, 2017, pages 185-186; of record).
The art at the time of filing also provided enabling guidance for determining the efficacy of psychiatric disorder drug treatments, including the unreliability and lack of translational utility for animal models of psychiatric disorders. Nani et al. state that “many difficulties need to be overcome to find good animal models for PDs, due to their multifactorial origins, high heterogeneity and symptoms, as for instance the hallucinations and delusions, which usually cannot be easily assessed employing ordinary experimental animal models” and that “it is important to use them judiciously and avoid the over interpretations derived for the findings, as it is noticeable that the results obtained on experimental animals are not necessarily confirmed in clinical studies” (Nani et al. IntechOpen, pages 1 and 9; of record). Nestler and Hyman state that, “perhaps the greatest disappointment with existing animal models of neuropsychiatric disorders is that they have failed, over several decades, to predict treatment efficacy in humans for previously unknown mechanisms of action” (Nestler and Hyman. Nature Neuroscience, 2010, page 1168; of record).
Furthermore, National Academies of Sciences, Engineering, and Medicine. 2019. Advancing gene-targeted therapies for central nervous system disorders: Proceedings of a workshop. Washington, DC: The National Academies Press. Editors: Stroud et al., 2019 Sep 20 (hereafter “Stroud”) teaches,
“Although scientists have begun to tackle complex polygenic disorders with gene therapy, they have not yet begun to apply this therapeutic approach to psychiatric disorders, said Hyman. He asserted that the time has come to think about this challenge while recognizing that clinical applications are a long way off.
Although neuropsychiatric disorders are highly heritable, all common neuropsychiatric disorders are highly polygenic, with phenotypes resulting from myriad small genetic nudges rather than a large genetic shove, said Hyman. He noted that this complicates efforts to identify which genes could be targeted…
Schizophrenia, however, is far more complex, said Hyman, with hundreds of genome-wide significant loci identified and extreme phenotypic heterogeneity (Huckins et al., 2019). He described a tool that could help scientists roughly stratify affected individuals at a genetic level by creating, for each individual, a weighted sum of risk alleles across the entire genome to produce a polygenic risk score (PRS). The PRS enables stratification of subjects by severity of genetic loading and permits identification of shared common variant risk across phenotypes, said Hyman. It can also help identify important genetic pathways and potentially identify targets for gene therapy interventions, he said. For example, about 70 percent of genome-wide association study (GWAS) hits in AD studies are expressed in microglia and are thought to be involved in inappropriate synapse elimination, said Hyman. He speculated that in schizophrenia, although none of the GWAS hits are expressed in microglia, there may be similar biological processes reached through different pathways such as genes encoding synaptic proteins and complement proteins that signal to microglia, adding that useful target selection can sometimes emerge from analysis of these pathways. What is important, he said, is to understand the biology. Transgenic animal models would require vastly improved methods of multiplexing using gene editing technologies.”(Emphasis added see under “Developing Gene-Targeted Therapies of Psychiatric and Neurodevelopmental Disorders”).
The specification as filed does not provide guidance that overcomes this unpredictability recognized in the relevant art at the time of filing.
The existence of working examples:
The specification discloses that STAB1 loss-of-function variants are associated with increased grey matter volume in brain regions. These variants show an association with improved cognitive function. Additionally, common variants near STAB1 are strongly linked to psychiatric disorders, with decreased STAB1 expression correlating with reduced risk for these disorders. One specific variant (rs11921116) is associated with better MRI outcomes and reduced risk for psychiatric disorders like bipolar disorder and schizophrenia. However, apart from disclosing that STAB1 variants are associated with beneficial effects on brain health, the specification discloses no working examples of administering a STAB1 inhibitor in any experimental system, including cell lines, animal models or human subjects, to demonstrate that the recited inhibitors will result in any treatment of a psychiatric disorder or a psychiatric disorder-associated MRI phenotype.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works, but one of the ability to make and use (i.e., practice) with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is in vivo treatment of schizophrenia or bipolar disorder type II, a person having skill in the art would have to perform multiple further experiments, in human clinical trials, or in animal models that are predictive of treatment in schizophrenia and bipolar type II disorder in order to demonstrate the invention could be used with a reasonable expectation of success.
The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any psychiatric disorder and/or a psychiatric disorder-associated MRI phenotype. Therefore, the instant claims are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
It is noted that in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Response to Arguments
With respect to the written description rejection of claims under 35 U.S.C. 112(a), Applicants’ arguments in view of the amendment to the claims are persuasive. Accordingly, the rejection has been withdrawn.
With respect to the enablement rejection of claims under 35 U.S.C 112(a), Applicants’ arguments have been fully considered, but are not persuasive. Applicant argues that the amendment makes it clearer what the is actually claimed: The treatment of schizophrenia or bipolar disorder type II with small molecule drug compounds known and currently used to treat these diseases, in combination with a STAB 1 inhibitor (such as an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a STAB 1 nucleic acid molecule) that decreases expression and/or activity of STAB1 polypeptide in a cell in the subject. Applicant believes that the now claimed subject matter certainly has utility in view of the extensive data provided in the application, that the skilled artisan would be able to practice the subject matter of the amended claims without undue experimentation (primarily because the treatment includes compounds known to be effective for treatment), and that the Office's arguments are not applicable to the claims as amended.
In response, Applicants’ arguments in view the amendment are not persuasive because the claims explicitly encompass treating schizophrenia or bipolar disorder type II using a method the requires the administration of an nucleic acid inhibitor of STAB1 expression to a subject. As indicated in the rejection above, the prior art teaches that there are no known examples of treating schizophrenia or bipolar disorder type II (or any other psychiatric disorder) using a nucleic acid inhibitor of gene expression. The prior art teaches one hurdle that must be overcome is the delivery of oligonucleotides across the blood brain barrier. The working example provided does not inform one of skill in the art how to overcome this hurdle. Furthermore, even if delivery of the nucleic acid inhibitor was overcome, the prior art teaches that it is unpredictable whether or not inhibiting expression of STAB1 would have a therapeutic effect at least because the use of genomics to identify gene variants that point directly to new targets for treatment is unreliable, and determining the efficacy of the treatment would be difficult because of the unreliability and lack of translational utility for animal models of psychiatric disorders including schizophrenia and bipolar disorder type II (see above). Given the lack of guidance on how to overcome at least these art-recognized problems, Applicants’ arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to J. E. Angell whose telephone number is (571)272-0756. The examiner can normally be reached Monday-Friday (8:30-5:00).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
Prosecution Insights