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 .
Drawings
The drawings filed on 3/29/24 are objected to for the following reasons:
37 C.F.R. 1.84 states “Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
In the current case, the words in Figures 3A-3C, 4A-4B (seem to be same drawing), 5A, 7A, 10, 11B, 13, 15, 16B, and 17 are not fully legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim recites ANKRD11 and NSD1, which are abbreviations. At the first recitation of an abbreviation, the claim is required to recite what the abbreviation stands for. Appropriate correction is required.
Claim 19 is objected to because it recites SEQ ID NOs: 40-11, which is not sequential. Given that ASO 29-33 are sequential in number, it is believed that applicant intends to recite SEQ ID NOs: 40-44. Appropriate correction is required.
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 1-20 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 claims recite that the antisense oligomer binds to a targeted portion of the pre-mRNA and modulates binding of “a factor involved in splicing” of the poison exon.
The specification discloses specific antisense oligomers 15 or 20 nucleotides in length that are fully complementary to specific portions of specific target sequences, which is not representative of the entire claimed genus of any antisense oligomer that is complementary at any level (i.e. 2 nucleotides) of any portion of any length (i.e. 2 nt) of the pre-mRNA of any ANKRD11 or NSD1 target sequence.
Th specification does not adequately describe the structure required for the antisense oligomer to achieve the recited function of modulating binding to a factor involved in splicing of the poison exon.
Additionally, the specification does not adequately describe which factors are involved in splicing of the poison exon. Therefore, one would not be able to readily envision which antisense oligomers necessarily have the structure to bind to any portion of any pre-mRNA of any ANKRD11 or NSD1 sequence and result in modulation of binding of any factor involved in splicing of any poison exon.
The claims recite exon 3x in the ANKRD11 gene, exon 4x in the ANKRD11 gene, and exon 11x in the NSD1 gene. Without further description of the specific sequence required, one would not be able to readily envision which specific exon is being required. Exon 3x in the ANKRD11 gene and exon 4x in the ANKRD11 gene do not appear to refer to a specific exon in the art.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, it appears that the structure is required have more specificity to a given target. For example, Stein (The Journal of Clinical Investigation, 2001, 108, 5, 641-644) teaches that if the antisense oligonucleotide is either too long or too short, an element of specificity is lost. At the present time, the optimal length for an antisense oligonucleotide seems to be roughly 16–20 nucleotides (page 641).
Nedorezova et al. (Theranostics, 2022, Vol. 12, Issue 16, 7132-7157) teach that to ensure tight binding, a typical oligonucleotide gene therapy agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma (abstract). The instant claims read upon an enormous possible genus of antisense oligomers that bind to any targeted portion at any length, which would not likely have the structure required for the function.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for antisense oligomers within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for increasing or decreasing ANKRD11 or NSD1 via delivery of specific antisense oligonucleotides for each outcome in vitro, does not reasonably provide enablement for a method for increasing or decreasing the expression of ANKRD11 or NSD1 via delivery of the same antisense oligomer, or via broad systemic in vivo delivery of any antisense oligomer meeting the broadly recited structural limitations, or for treating any disease or condition via any mode of delivery in vivo. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(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, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method for increasing or decreasing the expression of ANKRD11 or NSD1 via delivery of the same antisense oligomer, or via broad systemic in vivo delivery of any antisense oligomer meeting the broadly recited structural limitations, or for treating any disease or condition via any mode of delivery in vivo.
The specification demonstrates delivery of specific oligomers that fully target specific sites in a specific ANKRD11 or NSD1 sequence and result in inhibition of the specific poison exon targeted; and delivery of specific oligomers that fully target specific sites in a specific ANKRD11 or NSD1 sequence and result in upregulation of the specific poison exon targeted. However, the instant claims recite the outcome of increasing or decreasing the expression via delivery of the same genus of oligomers. Clearly a specific oligomer would not have both outcomes.
Not only does the specification not draw an adequate nexus between delivery of the instantly recited genus and both outcomes, but also does not draw an adequate nexus between delivery of the instant genus of oligomers, or even the oligomers of claims 19 and 20 and the predictable outcome of treatment of any disease condition as recited in instant claim 6 or any specific species. The gene walk demonstrated by applicant is not enabling for broad systemic delivery of any oligomer of the instantly recited claim language and the predictable outcome of treatment of any specific disease.
For example, Stein (The Journal of Clinical Investigation, 2001, 108, 5, 641-644) teaches that if the antisense oligonucleotide is either too long or too short, an element of specificity is lost. At the present time, the optimal length for an antisense oligonucleotide seems to be roughly 16–20 nucleotides (page 641).
Nedorezova et al. (Theranostics, 2022, Vol. 12, Issue 16, 7132-7157) teach that to ensure tight binding, a typical oligonucleotide gene therapy agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma (abstract). The instant claims read upon an enormous possible genus of antisense oligomers that bind to any targeted portion at any length, which would not likely result in increase or decrease of each of the recited targets or the treatment of any disease state which encompasses an enormous genus of diseases that have not been shown to be reliant upon either of the recited targets alone.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any antisense oligomer meeting the broadly recited structural limitations in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful increase and decrease of each of the recited targets and the treatment of any possible disease. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8, 11-14, 17, and 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Aznarez et al. (GB 2610100).
Aznarez et al. teach: Described are methods of modulating nonsense mediated RNA decay (NMD). An antisense oligonucleotide targeting an NMD-inducing exon in a pre-mRNA is contacted with a target cell. The oligonucleotide modulates the splicing of the NMD exon such that the levels of transcript producing active protein is increased. The target mRNA produces SYNGAP1 protein. Also described are antisense oligomer therapeutic agents, and their use in therapy (abstract).
Aznarez et al. teach: [0003] Described herein, in certain embodiments, is a method of modulating expression of a target protein, by a cell having an mRNA that comprises a non-sense mediated RNA decay-inducing exon (NMD exon) and encodes the target protein, the method comprising contacting a therapeutic agent to the cell, whereby the therapeutic agent modulates splicing of the NMD exon from the mRNA, thereby modulating level of processed mRNA encoding the target protein, and modulating the expression of the target protein in the cell, wherein the target protein is NSD1 (instant claims 1 and 17).
Aznarez et al. teach: [0004] Described herein, in certain embodiments, is a method of treating a disease or condition in a subject in need thereof by modulating expression of a target protein in a cell of the subject, comprising: contacting the cell of the subject with a therapeutic agent that modulates splicing of a non-sense mediated mRNA decay-inducing exon (NNID exon) from an mRNA in the cell, wherein the mRNA comprises the NNID exon and encodes the target protein, thereby modulating level of processed mRNA encoding the target protein, and modulating expression of the target protein in the cell of the subject, wherein the target protein is NSD1 (instant claim 6).
Aznarez et al. teach: The condition is Sotos syndrome [0019] (instant claim 8).
These compositions and methods include antisense oligomers (AS05) that can cause exon skipping, e.g., pseudoexon skipping, and promote constitutive splicing of NSD1.
Aznarez et al. teach that the ASO targets exon 11x of a NSD1 NW containing pre-mRNA comprising NIE exon 11 (page 46) (instant claims 1, 5, 8, 14, and 17). It is noted that Aznarez et al. is not required to teach that NSD1 exon 11x is a poison exon. This is defined by instant claim 1. Aznarez et al. anticipates the instant limitations regarding a poison exon by targeting an exon that is instantly recited as a poison exon.
Aznarez et al. teach that the antisense oligomer interferes with binding of the factor involved in splicing of the exon to a region of the targeted portion. The targeted portion is proximal to the exon; or the targeted portion is about 1 to 1500 nucleotides upstream or downstream of the exon [0006] (instant claims 2-4, 11-13, and 18).
Therefore, the claims are anticipated by Aznarez et al.
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.
Specific to NSD1:
Claim(s) 9, 10, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aznarez et al. (GB 2610100), as applied to claims 1-6, 8, 11-14, 17, and 18 above, and further in view of Martin-Herranz et al. (Genome Biology (2019) 20:146, 1-19).
Although Aznarez et al. teach that the condition to be treated can be Sotos syndrome, Aznarez et al. do not teach that the condition is aging or cancer.
However, it would have been obvious to treat a patient with aging or cancer with the method of Aznarez et al. because Martin-Herranz et al. teach that NSD1 modulation modulates the epigenetic maintenance system in humans which controls the rate of aging (page 1).
Martin-Herranz et al. teach that NSD1 causes Sotos syndrome and that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients (page 1).
Martin-Herranz et al. teach that there is a higher cancer predisposition in Sotos patients (page 6).
Martin-Herranz et al. teach that Sotos syndrome accelerates epigenetic aging (page 2). Therefore, one would expect for the method of Aznarez et al. to treat Sotos, aging, or specific cancers.
Although Aznarez et al. teach targeting the antisense oligomer to exon 11x of NSD1, Aznarez et al. are silent as to the specific sequence of the oligomer. However, selection of an oligomer within the exon of Aznarez et al. is done by methods routine to those in the antisense art. It would have been obvious and a matter of design choice to select one of the instantly recited sequences within the target exon disclosed by Aznarez et al. (instant claim 20).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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, Neil Hammell can be reached at 571-270-5919. 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.
/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights