DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection (on 10/14/2025). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/12/2025 has been entered.
Upon entry of the 09/12/2025 amendment, claims 1, 15-18, 20-29, 31-33 are pending.
Claim Rejections - 35 USC § 112(a)
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 15-17, 24-26, 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims encompass detecting the presence or absence of a variant nucleic acid molecule that encodes a STAB1 predicted loss-of-function polypeptide(e.g., see claims 15, 24). Accordingly, the claims encompass a genus of variant nucleic acid molecules encode a STAB1 predicted loss-of -function polypeptide. Accordingly, the claims required the possession of the claimed genus of variant nucleic acid molecules; however, the specification does not provide an adequate written description of the claimed genus.
As indicated in previous office actions, when analyzed in light of the specification, the claims encompass any variant nucleic acid molecule, including genomic nucleic acid molecules, mRNA molecules, and/or cDNA molecules, that encode a STAB1 predicted loss-of-function polypeptide.
The specification defines a variant nucleic acid molecule as “any nucleic acid molecule (such as, for example, genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) that contains one or more variations from a wild type nucleic acid molecule. In some embodiments, a variant nucleic acid molecule is any nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) encoding or resulting in a STAB1 polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function, or decreased expression thereof" (page 22; emphasis added), and that "representative variant nucleic acid molecules that decrease STAB1 expression and/or activity include, but are not limited to, loss-of-function variants (e.g., stop gain, stop lost, start gain, start lost, splice donor, splice acceptor, frameshift insertion, and frameshift deletion) and missense variants" (page 42).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure.
For the variant nucleic acid molecules, the specification discloses only one variant sequence, which includes the rs11921116 single nucleotide polymorphism (SNP) (pages 7 and 52-54). While the genus encompasses a large number of variants including variants molecules that differ in structure, the specification does not describe the complete structure of a representative number of species of the large genus of variant nucleic acid molecules
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic for a variant nucleic acid molecule is the functional requirement that the variant nucleic acid molecules “result in impaired expression and/or activity of STAB1.” It appears that there is no identification of any particular portion of a structure that must be conserved among the members of the genus for said activity.
Claims 16-17, 25-26, 33 depend on and encompass the inhibitors recited in claims 15 and 24 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, applicant’s disclosure of one species of a variant nucleic acid molecule (i.e., a genomic nucleic acid molecule having a nucleotide sequence comprising a guanine at a position corresponding to position 501 according to SEQ ID NO: 17) is not deemed sufficient to reasonably convey to one skilled in the art that applicant was in possession of the claimed broad genus of variant nucleic acid molecules. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus of variant nucleic acid molecules encompassed by the instant claims.
Claims 1, 15-18, 20-29, 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 have been amended to limited 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 treatment for a method of treating schizophrenia or bipolar type II disorder by administering any of a number of specific therapeutic agents. 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 a psychiatric disorder.
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 a psychiatric disorder, let alone 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 within the art.
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
Applicant's arguments filed 09/12/2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 112(a) (written description rejection) as set forth above, Applicant argues that the claims have been amended and are limited to treating schizophrenia or bipolar disorder type II but not bipolar type I, and detecting the presence or absence of a variant nucleic acid molecule that encodes a STAB1 predicted loss-of-function polypeptide. It is noted that the written description issue is with respect to the genus of variant nucleic acid molecules that encode a STAB1 predicted loss-of-function polypeptide encompassed by the claims, and not with respect to schizophrenia or bipolar disorder type II. Applicant argues that “specific gene variants are not the central finding at all. Instead, they serve as tools to connect genes and there encoded proteins with particular disease conditions – in this case linking STAB1 with schizophrenia and bipolar disorder type II.”
In response, it is noted that the rejected claims (i.e., claims 15-17, 24-26, 33) specifically encompass the variant nucleic acid molecules as claims 15 and 24 explicitly recite the variant nucleic acid molecule limitation and the other claims are dependent claims not limited to a specific variant. Thus, the genus of variant nucleic acid molecules are critical to the claimed invention and appropriate written description for the claimed genus is necessary, even if applicant does not consider the variants the central finding at all.
Applicant argues that Examples 1 to 5 include extensive scientific studies that includes a variety of genetic markers to arrive at the indicated recognition. Applicant asserts that STAB1 has been studied extensively for decades, that structure-function modeling is well-established, that powerful computer-based tools are typically used to predict functional impact of amino acid substitutions, and that detection of nucleic acid variants has been a standard approach for many years.
In response, it is noted that Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
With respect to the rejection of claims under 35 USC 112(a) (enablement rejection) Applicant contends that the claims have been amended to limit the therapeutic agent and disorder and that the skilled artisan would be able to practice the claimed method without undue experimentation.
In response, Applicants are not persuasive because, as indicated in the rejection above, it is unpredictable to treat psychiatric disorders, including schizophrenia and bipolar disorder type II using genetic manipulation, which includes by gene knock-down using nucleic acid based expression inhibitors as is claimed, and there are no working examples in the specification nor are any similar type methods found in the prior art (or post-filing art) which overcome the unpredictability taught in the prior art.
Therefore, Applicant’s arguments are not persuasive.
Conclusion
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).
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637