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 .
Formal Matters
Original claims 1-17 were presented on 06/26/2023 and are pending and under examination.
Priority
This application is a division of U.S. Application No. 16/631,762, filed January 16, 2020, which is the U.S. National Stage application, pursuant to 35 U.S.C. §371, of PCT International Application No. PCT/US2018/042876, filed July 19, 2018, which claims the benefit of and priority to U.S. Provisional Application No. 62/534,532, filed July 19, 2017.
Information Disclosure Statement
Applicant’s Information Disclosure Statements filed 06/26/2023 and 07/30/2025 have been received and entered into the present application. As reflected by the attached, completed copies of form PTO-1449, the Examiner has considered the cited references to the extent that they comply with the provisions of 37 C.F.R. §1.97, §1.98 and MPEP §609.
Claim Rejections - 35 USC § 112(b)
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 1-6 and 10-17 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
"The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Here, a person of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed method, specifically the disorders intended to be encompassed by the claims (subject population).
Regarding “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”, the disclosure and claims recite such disorders are associated with a mutation in numerous genes (genes of Table 1) or in a gene selected from the group consisting of Adamts2, Bbx, BC049762, Bmp7, C430002E04Rik, E2f3, Enc1, Epas1, Etv6, Fam198b, G730013BO5Rik, Gab], Gramdlb, MbnI2, Otx2, Otx2osl, Phfl 7, Rbmsl, Rbp2, Runxl, Sfmbt2, Sh3g3, SIc38aI, S1c38a2,Slc38a4, Smocl, Sox2 and Tle3. Conspicuously absent from such disclosures are the actual mutations in such genes that are actually associated with a disorder. The only disorders actually described by Applicants are microphthalmia with limb anomalies (MLA) associated with a mutation in Smoc1 and placental defects associated with a mutation in Gab1 or Sfmbt2. A person of ordinary skill in the art would not know what subjects, out of all subjects that exist in the art, have “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting” because such disorders were not known in the art.
The prior art is replete with examples wherein a claimed agent that inhibits histone H3 lysine 27 methylation, e.g., inhibitors of EZH2, are administered to cells and/or subjects. See, for example, WO 2015/128837 A1, which teaches methods of treating cancer comprising administering to a subject the EZH2 inhibitor GSK126, which is expressly claimed in instant claim 15. WO ‘837 teaches the function of EZH2 in silencing genes via tri-methylating lysine 27 of histone H3 (p.1, l.22-25), the implication of EZH2 overexpression or overactivity in different types of cancer (p.5, l.25 to p.6, l.4), which overexpression is disclosed to result in an increase in H3K27me3 and to allow for aberrant transcriptional silencing of genes implicated in normal cellular homeostasis (p.6, l.21-25). It is unclear if subjects having cancer in which genes silenced, i.e., repressed, by H3K27me3 are intended by Applicants to fall within the scope of the claimed “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10 and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 10 depends from claim 1 and requires “a cell of the subject is contacted with the agent”. Claim 16 depends from claim 10 and requires “the cells is contacted in vitro or in vivo”. Claims 10 and 16 fail to further limit claim 1 from which they directly or indirectly depend because claim 1 requires “…treating a subject having a disorder…comprising administering to the subject an agent…”. Such administration to a subject will naturally cause the agent to contact “a cell of the subject” (claim 10) and is necessarily in vivo administration (Claim 16). Contacting a cell of subject in vitro as encompassed by claims 10 and 16 does not further limit claim 1 which requires administration “to the subject” (in vivo administration).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112 – 1st Paragraph, Written Description
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-17 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Claim 1 requires administering an agent that inhibits histone H3 lysine 27 trimethylation (H3K27me3) or an agent that “selectively removes trimethylation at lysine 27 of histone 3” to subjects having “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”.
Claims 2-6 require such disorders are associated with a mutation in numerous genes (genes of Table 1) or in a gene selected from the group consisting of Adamts2, Bbx, BC049762, Bmp7, C430002E04Rik, E2f3, Enc1, Epas1, Etv6, Fam198b, G730013BO5Rik, Gab], Gramdlb, MbnI2, Otx2, Otx2osl, Phfl 7, Rbmsl, Rbp2, Runxl, Sfmbt2, Sh3g3, SIc38aI, S1c38a2,Slc38a4, Smocl, Sox2 and Tle3.
Claim 13 requires the agent is an inhibitor of histone H3 lysine 27 trimethylation (H3K27me3).
Claim 14 requires the agent is a small molecule compound, polypeptide, or polynucleotide.
The disclosure names 7 species of agent that inhibits histone H3 lysine 27 trimethylation, all of which are small molecule compounds. Specifically, the only disclosed species of “an agent that inhibits histone H3 lysine 27 trimethylation (H3K27me3)” are tazemetostat, DZNep, GSK373, GSK126, EL1, Epz005687, and CPI-169. See Specification at p.43, l.21-23; Claim 15. For example, Applicants do not disclose or describe the amino acid or nucleotide sequences of any polypeptide or polynucleotide inhibitor of H3K27 methyltransferase.
Notably, the disclosed species are not even inhibitors of H3K27 methyltransferase per se, but rather are inhibitors of EZH1, EZH2, PRC2, PRC2-Ezh1, or PRC2-Ezh2. Thus, at best what Applicants describe are inhibitors of EZH1, EZH2, PRC2, PRC2-Ezh1, or PRC2-Ezh2, not general inhibitors of the claimed genus of “histone H3 lysine 27 trimethylation”.
The only disorders actually described by Applicants are microphthalmia with limb anomalies (MLA) associated with a mutation in Smoc1 and placental defects associated with a mutation in Gab1 or Sfmbt2.
A person of ordinary skill in the art would not be able to predict the operability of any given small molecule compound, polypeptide, or polynucleotide to inhibit histone H3 lysine 27 trimethylation, let alone treat “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that 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, for purposes of the written description inquiry, is whatever is now claimed (see page 1117).
Here, Applicants want to preclude from the public administering any small molecule compound, polypeptide, or polynucleotide that inhibits any histone H3 lysine 27 trimethylation, regardless of its mechanism of action, to subjects having any “disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”. To support such broad protection and right to exclude, Applicants describe the claimed invention only by carry out in vitro testing demonstrating that H3K27me3-repressed alleles exist in mouse zygotes and mouse embryos at certain stages of development. However, other than a broad, general hypothesis that “an agent that inhibits histone H3 lysine 27 trimethylation” will be effective to treat disorders “associated with” histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting, Applicants did not contact any cell or administer to any subject any compound of the invention.
As the courts have repeatedly stated, the purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.” Rochester, 358 F.3d at 920 (quoting Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345 [54 USPQ2d 1915] (Fed. Cir. 2000)).
Here, Applicants contribution to the field of art is the identification of a DNA methylation-independent imprinting mechanism mediated by H3K27me3 in mouse preimplantation embryos, i.e., basic scientific research on the potential role of histone H3 lysine 27 trimethylation on genomic imprinting in mouse embryotic development. As evidenced by RAAS ET AL. (Trends in Genetics, January 2022, Vol. 38, No. 1, pages 82-96)1, at the time the application was filed a person of ordinary skill in the art would not have known what cells, out of all cells that exist in the art, have an imprinting mechanism mediated by H3K27me3, other than those mouse preimplantation embryos utilized by Applicants. Specifically, even in 2022, over four years after Applicants’ disclosure, Raas et al. teach that “[a]n important question is whether the noncanonical imprinting as observed in mice is also present in humans” (Rass et al. at p.91). If such was still not known in 2022, it most certainly was not known in 2017 when Applicants filed their application.
At best, Applicant’s Specification directs one to screen random compounds to determine whether they inhibit any component involved in histone H3 lysine 27 trimethylation and then figure out, through trial-and-error testing, which of these compounds are capable of activating a H3K27me3 repressed allele in a cell and then which of those compounds are capable of treating any particular “disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”. This activity would require “excessive trial and error experimentation” (FF 14). See In re ʼ318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
One of skill in the art would not recognize from the disclosure that the applicant was in possession of treating subjects having “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting” comprising administration of “an agent that inhibits histone H3 lysine 27 trimethylation” or “an agent that selectively removes trimethylation at lysine 27 of histone 3”. 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).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112, 1st Paragraph (Scope of Enablement)
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 1-17 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 activating a H3K27me3 repressed allele within an imprinting control region of mouse sperm cells, oocytes, or embryos, does not reasonably provide enablement for “treating a subject having a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”. 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 use the invention commensurate in scope with these claims. This is a Scope of Enablement rejection.
The claims broadly encompass treating a subject having “a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting” comprising administration of “an agent that inhibits histone H3 lysine 27 trimethylation” or “an agent that selectively removes trimethylation at lysine 27 of histone 3” to the subject. See Claim 1.
At the time the application was filed, H3K27me3-mediated genomic imprinting was completely unknown as were disorders “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”. In other words, alleles being repressed in an imprinting control region of a cell by H3K27me3 was not known in the art until Applicants’ earliest effective filing date (July 19, 2017) and the first publication of their work on July 19, 2017 (INOUE ET AL., Nature, July 27, 2017, vol. 547, pages 419-424) (Published Online July 19, 2017). Thus, the only guidance and direction for making and using the claimed invention available to a person of ordinary skill in the art at the time the application was filed was Applicants’ disclosure. The state and predictability of the art was completely unknown at the time the application was filed because what Applicants disclose and claim is the first such disclosure in the art of alleles being repressed in an imprinting control region of a cell by H3K27me3.
As evidenced by RAAS ET AL. (Trends in Genetics, January 2022, Vol. 38, No. 1, pages 82-96)2, Applicants have not enabled a person of ordinary skill in the art to activate a histone H3 lysine 27 trimethylation (H3K27me3) repressed allele within an imprinting control region of cells other than mouse zygotes and preimplantation embryos. Specifically, even in 2022, over four years after Applicants’ disclosure, “[a]n important question is whether the noncanonical imprinting as observed in mice is also present in humans” (Rass et al. at p.91). Furthermore, even in 2022, addressing this question was still challenging from a technical perspective due to the “generally low frequency of polymorphisms between human alleles, complicating sequencing-based allele-specific epigenetic assay” (Id. at p.91-92). Indeed, “recent analysis shows that at the eight-cell stage, H3K27me3 is nearly absent in humans”, which implies that, in contrast to mice, “early allelic differences in the localisation of H3K27me3 are likely not maintained during early human development, and therefore H3K27me3 might not function as an imprinting mark in humans” (Id. at p.92). Raas et al. conclude that in 2022, over four years after Applicants’ earliest effective filing date, “further research is needed to determine whether indeed oocyte H3K27me3-mediated gene imprinting is absent in humans” (Id.). This post-filing art is prima facie evidence that a person of ordinary skill in the art at the time the application was filed could not have predictably treated disorders “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting” in a subject by administering to the subject with an agent that inhibits histone H3 lysine 27 trimethylation because “H3K27me3 might not function as an imprinting mark in humans” and it was not even known at the time the application was filed what cells, if any, have H3K27me3-mediated gene imprinting, other than those mouse cells used by Applicants. Indeed, MONK ET AL. (PNAS, April 25, 2006, vol. 103, no. 17, pages 6623– 6628) disclose that in contrast to the maternal expression observed in the mouse, the human expression of the human orthologues of all reported mouse placental-specific imprinted genes is largely biallelic. Thus, at the time the application was filed a person of ordinary skill in the art would not predict that the studies carried out by Applicants in mouse preimplantation embryos would extend to cells of other mammals, particularly humans, let alone to the treatment of disorders “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”.
Furthermore, the contribution of H3K27me3 to repressing expression of any given gene in any given cell is not at all straightforward and predictable. Applicants posit that by simply inhibiting H3K27me3 any disorder “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting” can be treated in a subject. However, at the time the application was filed it was known that the absence of H3K27me3 only partially affects the expression of ICR-associated transcripts in a locus- and tissue-specific manner. See MAUPETIT-MEHOUAS ET AL. (Nucleic Acids Research, 2016, Vol. 44, No. 2, pages 621–635) at pages 628-630.
Working examples are limited to in vitro cell-based assays using DNase I-sequencing in mouse zygotes and preimplantation mouse embryos. Applicants did not, however, carry out any testing on other cells, let alone human cells, let alone in subjects. No doses of any agents whatsoever for administration to a subject are disclosed. Furthermore, Applicants also did not contact any cells with any agent that inhibits histone H3 lysine 27 trimethylation, let alone demonstrate that contacting a mouse zygote or preimplantation embryo with such an agent actually activates the transcription any repressed allele and treats any disorder. Rather, what Applicants have shown is that in mouse zygotes and some embryonic stages of mouse development, H3K27me3 potentially mediates genomic imprinting of specific genes. There is absolutely no evidence of such H3K27me3 mediated genomic imprinting in cells of any other organism, let alone humans. There is also no evidence that administering to a subject an agent that inhibits histone H3 lysine 27 trimethylation actually activates the transcription any gene and can be used to treat a disorder “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”. At bottom, Applicants have failed to establish a clear nexus between H3K27me3-dependent imprinting and any particular disorder, let alone a nexus between an inhibition of H3K27me3-dependent imprinting in a subject and treatment of any particular disorder. The guidance and direction provided by Applicants for carrying out the claimed invention amount to no more than a hypothesis that an agent that inhibits histone H3 lysine 27 trimethylation will necessarily be effective to treat disorders “associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting”, despite not a single working example demonstrating such effectiveness. Rather, this speculation based solely on Applicants’ determination that in mouse zygotes and preimplantation embryos expression of some specific alleles may be mediated by H3K27me3. However, even if, for example, microphthalmia with limb abnormalities, is associated with H3K27me3-dependent imprinting, this birth defect would have already occurred during development before an agent is even administered to a subject having the disorder.
The broad scope of the claims in view of the state and predictability of the art, the complete lack of working examples directed to the claimed invention, and post-filing evidence that “H3K27me3 might not function as an imprinting mark in humans” all weigh against enablement for the full scope of the claimed invention. A person of ordinary skill in the art would not be able to predict the operability of any given embodiment of the claims without carrying out undue experimentation.
Conclusion
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES D ANDERSON whose telephone number is (571)272-9038. The examiner can normally be reached on Monday-Friday, 8:30 am - 5:00 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/James D. Anderson/Primary Examiner, Art Unit 1629
UNITED STATES PATENT AND TRADEMARK OFFICE
400 Dulany Street
Alexandria, VA 22314-5774
Tel. No.: (571) 272-9038
1 The Federal Circuit in Amgen Inc. v. Sanofi, No. 17-1480 (Fed. Cir. 2017), citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 (Fed. Cir. 1983), held that post-filing evidence can be relevant to determining if claims meet the written description requirement of 35 U.S.C. 112, 1st Paragraph. Here, Raas et al. is cited as evidence that at the time the application was filed a person of ordinary skill in the art would most certainly not have known what cells have a H3K27me3-repressed allele within an imprinting control region of the cell.
2 The Federal Circuit in Amgen Inc. v. Sanofi, No. 17-1480 (Fed. Cir. 2017), citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 (Fed. Cir. 1983), held that post-filing evidence can be relevant to determining if claims are enabled. Here, Raas et al. is cited as evidence that at the time the application was filed a person of ordinary skill in the art would most certainly not have known what cells have a H3K27me3-repressed allele within an imprinting control region of the cell.