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 .
Priority
Applicant’s claim for the benefit of a prior-filed application 63/380,093 filed on 10/19/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) filed on November 14, 2023; July 12, 2024; August 16, 2024; October 29, 2029; December 27, 2027; June 16, 2025; July 8, 2025; and December 10, 2025 have been considered.
Status of Application/Claims
Claims 1-20, filed 10/19/2023, are pending. Claims 1-20 are the subject of the present Official action.
Claim Objections
Claims 7 and 19 are objected to because of the following informalities: The term “function variant” should read “functional variant”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation "the agent" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 1 refers to an expression vector but not to an agent. Claims 10 and 11 are dependent on Claim 9 and therefore are likewise rejected under 35 U.S.C. 112(b).
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 7 and 19 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 MPEP discusses the written description requirement in detail starting at § 2163. The following guidance is more thoroughly expounded upon therein. But in summary, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention. Such a review is conducted from the standpoint of one of skill in the art at the time the application was filed (see, e.g., Wang Labs. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art. Generally, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Satisfactory disclosure of a “representative number” depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Claims 7 and 19 recite, “The expression vector of …, wherein the nucleotide sequence encoding BCL11A comprises a nucleotide sequence that encodes human BCL11A of SEQ ID NO:2, or a function(al) variant thereof.” Attention is drawn to the “…or a functional variant thereof” language. Given a broadest reasonable interpretation (BRI), the claims read on any possible change in nucleotide sequence to SEQ ID NO:1 that encodes a functional BCL11A protein. While it would be obvious to one of ordinary skill in the art that silent substitutions may retain the function of the BCL11A protein product, the effect of every possible deletion, substitution, insertion, or post-translational modification on the biological activity of BCL11A is unknown.
In the specification, the instant case defines the term “a functional variant” of a gene product as referring to any modified gene product (by deletion, substitution, insertion, glycosylation, etc.) that retains at least 50% of the biological activity of the unmodified (wild-type) gene product in a competition assay. The specification has not reduced to practice any examples of a functional variant of BCL11A and thus does not present a representative sample to characterize the genus of functional variants of BCL11A. By claiming any functional variant that retains 50% of biological activity of wild-type BCL11A, the claims encompass embodiments of the recited SEQ IDs that will undoubtedly have structural and functional properties that are different from that described in the specification.
Many dysfunctional variants including disease-associated mutations and single nucleotide polymorphisms (SNPs) of BCL11A have been reported in the art. Abdulazeez et al. (PLoS One, 2019; hereinafter Abdulazeez) conducted an in silico study to examine a database of 11,463 SNPs of BCL11A and identified five of the most pathogenic non-synonymous SNPs that disrupt the BCL11A protein (S783N, D643N, G451S, K670R, and M313L). While computational studies offer a cost-effective approach to screen non-synonymous SNPs, Abdulazeez concludes that the in silico data must be validated in future experiments that reflect its biological context. Additionally, Dias et al. (American Journal of Human Genetics, 2016) reports an intellectual disability syndrome caused by missense mutations clustered in the amino-terminal region of BCL11A, disrupting localization, dimerization, and transcriptional regulatory activity of the protein. It is clear that prior studies have identified genetic variations in BCL11A that lead to disease caused by structural and functional changes to BCL11A protein transcripts. The prior art establishes that there would be experimentation required to produce a representative sample of the genus of all functional variants of BCL11A that retain 50% of its biological function as broadly claimed in the instant case.
Applicant has not produced a sufficient number of species to characterize the genus of every functional variant of BCL11A. Although Applicants may argue that it is possible to screen for functional variants, the court found in Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004 that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the chemical invention. Accordingly, Claims 7 and 19 are rejected because the specification fails to reasonably convey possession of the claimed subject matter under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Goldman et al. (WO 2019/246262 A2; hereinafter Goldman), in further view of Du et al. (Cerebral Cortex, 2021; hereinafter Du), Grostol Dietz et al. (Lancet Psychiatry, 2020; hereinafter Grostol Dietz), and Carrino et al (US 2006/0275794 A1; hereinafter Carrino).
With regard to Claims 1-2 and 4-5, Goldman teaches methods of delivering an expression vector with a glial progenitor cell (GPC)-specific promoter to modulate expression of BCL11B, which Goldman lists as an axon guidance and neuron projection gene. See Claims 40 and 11, 13, 15, 17, 19, 29, 48, and 49 of Goldman. Goldman teaches doing so for the purpose of treating or inhibiting onset of Huntington’s disease, which is considered a glial cell-related disorder. Goldman also teaches delivering modulators of the MYRF-regulated myelinogenic transcripts MAG and PLP1 and synapse gene BCAS1, which the instant case lists as markers of glial differentiation. Goldman also teaches delivery of modulators of BCAN, CCND2, MYC, and PCDH15, which the instant case lists as cellular youth markers. Modulating expression of the stated markers of glial differentiation and cellular youth meets the definition of cellular rejuvenation in the instant case. However, Goldman does not teach the modulation of BCL11A in GPCs.
Du teaches the cooperative functions of BCL11A and BCL11B in regulating the production and differentiation of cortical projection neurons. BCL11A expression is present in cortical neural progenitors and cortical projection neurons, whereas BCL11B expression is restricted to the cortical projection neurons. Deficiency of BCL11A led to reduced proliferation and premature differentiation of cortical progenitor cells, which is exacerbated when BCL11B is simultaneously deleted. BCL11A and BCL11B also jointly play a role in controlling timing of the neurogenesis-to-gliogenesis switch, which is accelerated in BCL11A/B double knockout mice. BCL11A evidently plays a critical role in the regulation of differentiation of cortical neuron progenitors into cortical neurons, astrocytes, and oligodendrocytes.
One of ordinary skill in the art would have been motivated to include BCL11A as a glial cell differentiation regulation gene listed by Goldman to be modulated in the method of Goldman. See Claims 1, 5, and 7 of Goldman. One of ordinary skill in the art would have been motivated to make such an inclusion because Du teaches a critical role of BCL11A in cortical progenitor cell differentiation into glial cells and production of cortical projection neurons. Accordingly, one of ordinary skill in the art would understand that modulating BCL11A would provide for more efficacious modulation of glial cell differentiation for the purpose of treating or inhibiting onset of a glial cell-related disorder. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because all the reagents and detailed instructions for their use were described in Goldman and the secondary reference Du.
Du additionally teaches the redundant functions of BCL11A and BCL11B in regulating the development of deep-layer cortical projection neurons. In BCL11A/B double knockout mice, more severe defects in gene expression and axonal projection were observed in deep-layer neurons compared to the summation of the defects observed in the BCL11A knockout mice and BCL11B knockout mice, indicating that the two genes may inhibit high-level expression of each other and act redundantly to promote deep-layer neuron subtype identities.
One of ordinary skill in the art would have been motivated to replace BCL11B in the method of Goldman with BCL11A of the secondary reference. One of ordinary skill in the art would have been motivated to make such a substitution because Du teaches a critical role of BCL11A in axon guidance and extension. Accordingly, one of ordinary skill in the art would understand that substituting BCL11B for BCL11A would provide for more efficacious modulation of axon guidance for the purpose of treating or inhibiting a glial cell-related disorder. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because all the reagents and detailed instructions for their use were described in Goldman and the secondary reference Du.
With regard to Claim 3, as stated above Goldman teaches treating Huntington’s disease which is considered an age-related white matter disease.
With regard to Claim 6, Goldman does not teach treating a neuropsychiatric disorder.
Grostol Dietz teaches the role of glial cells in the development of schizophrenia, including studies that suggest that abnormalities in differentiation competence of GPCs leads to failure in the morphological and functional maturation of oligodendrocytes and astrocytes. All four glial cell types were reported to show dysregulated patterns of gene expression in postmortem tissue from patients with schizophrenia in both cortical and subcortical regions. Additionally, the cell cycle of GPCs was found to be dysregulated in patients with schizophrenia, resulting in arrested differentiation and delayed maturation of oligodendrocytes and astrocytes. Grostol Dietz suggests that targeting glial pathology offers new mechanisms to modify pathogenesis of schizophrenia.
Accordingly, one of ordinary skill in the art would have been motivated to consider schizophrenia a glial cell-related disorder and target GPC differentiation for the purpose of treating schizophrenia in the method of Goldman based on the teachings of Grostol Dietz. One of ordinary skill in the art would have been motivated to do so because Grostol Dietz teaches the key role of GPC differentiation in the pathogenesis of schizophrenia and suggests the development of treatment routes targeting glial cells. Accordingly, one of ordinary skill in the art would understand that targeting GPC differentiation would provide for more efficacious treatment of schizophrenia which is a glial cell-related disorder. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because all the reagents and detailed instructions for their use were described in Goldman and the secondary references.
With regard to Claims 7 and 19, Carrino lists the sequence of BCL11A claimed in the instant case as SEQ ID NO:2. The BCL11A sequence listed by Carrino is the consensus sequence of BCL11A.
One of ordinary skill in the art would have been motivated to replace BCL11B in the method of Goldman with the consensus sequence of BCL11A listed by Carrino, based on the teachings of the secondary reference Du stated above. One of ordinary skill in the art would understand that the use of the consensus sequence to modulate BCL11A would provide for more efficacious modulation of glial cell differentiation and axon guidance as taught by the secondary references for the purpose of treating or inhibiting onset of a glial cell-related disorder. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because all the reagents and detailed instructions for their use were described in Goldman and the secondary reference Du.
With regard to Claim 8, Goldman teaches delivery of gene modulators by biodegradable microspheres, microparticles, nanoparticles, and liposomes, which are considered non-viral expression vectors. See paragraphs 0063, 0066, and 0069-0072 of Goldman.
With regard to Claims 9-11, Goldman teaches delivery of viral expression vectors encoding modulators of BCL11B including lentivirus vectors, adenovirus vectors, and adeno-associated virus vectors. See paragraphs 0041 and 0064 of Goldman.
With regard to Claim 12, Goldman teaches using a promoter specific separation technique to select a glial cell-specific promoter. See paragraph 0116 of Goldman.
With regard to Claims 13-14, Goldman teaches the use of inducible or regulatable promoters and a tet-on promoter system. See paragraphs 0064 and 0145 of Goldman.
With regard to Claim 15, Goldman teaches methods of delivering human GPCs and modulators of MYC expression. See Claims 40, 7, 29, and 31 of Goldman. Goldman also teaches administering GPCs genetically modified to express a protein of interest. See paragraph 0121 of Goldman.
With regard to Claim 16, Goldman teaches methods of delivering human GPCs and modulators of OLIG2 and SOX10 expression. See Claims 40, 1, 3, 5, 7, 9, 31, 33, and 35-36 of Goldman. Goldman also teaches administering GPCs genetically modified to express a protein of interest. See paragraph 0121 of Goldman.
With regard to Claim 17, as stated above Goldman teaches delivery of a gene modulator using viral expression vectors including lentiviral and AAV vectors with a regulatory element.
However, Goldman does not teach the delivery of a gene modulator for BCL11A. As stated above, one of ordinary skill in the art would have been motivated to replace BCL11B in the method of Goldman with BCL11A of the secondary reference Du.
With regard to Claim 18, Goldman teaches using a promoter specific separation technique to select a glial cell-specific promoter. See paragraph 0116 of Goldman.
With regard to Claim 20, Goldman teaches administering GPCs genetically modified to express a protein of interest. See paragraph 0121 of Goldman.
Conclusion
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/H.P./ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631