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 .
Specification
The use of the term “Dacogen” on page 22 and “Trizol” on page 56 on “Lipofectamine” page 78, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please review the entire specification for any other trade name or marks.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 2-5, 8-10 and 14-24 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 an inactive X-linked allele in a female or hemizygous mammalian subject comprising administering RG108 or decitabine and a nucleic acid, which targets XIST long noncoding RNA (lncRNA) to reduce XIST lncnRNA in the cell, does not reasonably provide enablement for activating an inactive X-linked allele in a genus of cells or subjects. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention embraces activating an inactive X-linked allele in a cell, preferably a cell of a female heterozygous or male hemizygous subject; comprising administering a DNA methyltransferase (DNMT) inhibitor and a nucleic acid inhibitor of Xist RNA. The limitation to subjects after preferably does not limit the cell to either of these types of cells because preferably does not indicate that the cell is limited to these two types of cells.
In view of instant claims 8-10, the claimed invention embraces treating, alleviating, or curing an X-linked disorder in the subject. The specification does not appear to provide a definition of a therapeutically effective amount and/or a working example in a living subject. The subject could be mammalian or non-mammalian, including primates, human, mice, birds, insects, organisms. The specific role and function of X chromosome differ across species.
At the time of the effective filing date, a person of skill in the presumed to have knowledge of the claimed invention would also possess the knowledge that around 2,000 X-linked genes are on the X chromosome and about 10% are not inactive by X inactivation.
The skilled artisan would also understand that the biology of X chromosome is complicated and not completely understood. X-chromosome inactivation (XCI) is dependent on different factors that suppress XCI (see Hysolli et al. (Cell Cycle 11: 229-235, 2012, cited on an IDS). This could include the balance between Xist and Tsix.
The claimed invention embraces activating an inactive X-linked allele in a genus of cells, including cells of a female heterozygous or male hemizygous subject comprising administering a specific DNMT inhibitor (RG108 or decitabine) and a nucleic acid inhibitor targeting Xist RNA.
In view of claims 8-10, the claimed invention embraces treating, alleviating, or curing an X-linked disorder in the female or male subject. Other than inactivation by Xist RNA, the specification does not disclose other types of inactivation of an X-linked allele in a cell of female heterozygous or hemizygous male mammalian subject could be activated using either claimed DNMT inhibitor and an inhibitory nucleic acid targeting Xist RNA.
Furthermore, results observed in a cell line might not reasonably extrapolate to the same results observed in another cell type or a subject (non-mammalian) without an undue amount of experimentation due to the bio-kinetics of a subject of a more complex system. In the specification, the applicant identified proteins that interact with XIST and screened the interactors in a fibroblast cell line. The applicant also disclosed that locked nucleic acid (LNA) targeting Xist and DNMT inhibitor reactivated an X chromosome in immortalized fibroblast from a female with Rett syndrome. It was observed that mecp2 was reactivated in the cell line. In view of the therapeutically effective amount, the claimed invention broadly embraces treating, preventing or curing a disease or disorder and the specification does not disclose that the reactivation of an inactive X chromosome can treat or prevent a disease phenotype in a genus of subjects.
With respect to a genus of cells, the specification appears to provide working examples for a fibroblast cell line from a mammalian female or undifferentiated ES murine cells, but the claimed method is not considered enabled for the genus of cells, including cells in a subject (e.g., non-mammalian) without an undue amount of experimentation. The claimed invention embraces a large number of cells (e.g., in vitro and in vivo; differentiated and undifferentiated, placental mammal, non-placental mammalian).
The prior art teaches the unpredictability of reactivating X chromosome in a genus of cells (X-reactivation might be irreversible in differentiated cells). "Notably, Xist is specific for placental mammals with no orthologous RNA described in marsupial mammals or any vertebrate species to date (Ohhata et al. Cell Mol. Life Sci. 2013 70: 2443-2461, cited on an IDS)." A person of skill of art was aware that DNA methylation (5-aza-deoxycytidine) has been shown to induce stochastic Xi reactivation in somatic cells (Csankovszki et al. J Cell Biol. 2001, 153, 773-784, cited on an IDS).
The limited working examples provided by the specification does not provide enablement for a genus of cells. The prior art of record discloses that a skilled artisan could not reasonably extrapolate from one type of cell line to a genus of cells. "While a lot of work has been focused on XCI at the stem cell level, not much is being done on differentiated cells (Hysolli, supra, page 235)." Cantone et al. (Phil. Trans. R. Soc. 372: page 1-8, 2017, cited on an IDS) teaches, "Recent studies, however, have shown that XCI is remarkably different in rodents as compared to humans and other mammalian species (page 2)." “ Xist RNA and DNA methylation contribute differently to silencing of two X-linked genes (Csankovszki et al. J Cell Biol. 2001, 153, 773-784, cited on an IDS).”
"A significant amount of species differences has been uncovered in recent studies and has to be taken into account when extrapolating findings across species (page 2444, Ohhata, supra)." Also see page 2448, right column, first full paragraph of Ohhata. Ohhata discloses, "Effective treatment for reactivation of the Xi are likely correlated with widespread disruption of epigenetic patterns elsewhere in the genome that could cause adverse effects (page 2456)." "Further studies are therefore needed before such approaches can be adopted in the clinic (page 2456 of Ohhata et al., supra)."
In view of the reasons set forth above, the skilled artisan cannot reasonably extrapolate from the limited teaching or generic contemplations in the specification to the genus of cells (including in a human) without an undue amount of experimentation.
It appears that different cell types are controlled by different combinations of factors and the skill artisan cannot extrapolate from reactivating an X chromosome in one cell type to another type of cell with a reasonable expectation of success. Thu, the specification appears to only provide enablement for mammalian cells.
Furthermore, with respect to claims 8 and 9, other than contemplating treating, alleviating, or curing a subject having an X-linked disorder, the specification does not teach how to use the claimed invention. The limitation 'therapeutically effective amount' is broad and reads on any amount of the inhibitors. The specification does not disclose any amount that is sufficient to cure, alleviate or partially arrest the clinical manifestation of any disorder. The specification does not provide a working example of administering a therapeutically effective amount of the specific DNMT inhibitors and a nucleic acid targeting Xist RNA to treat an X-linked disorder.
Thus, the instant claims are not considered fully enabled.
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 2-5, 8-10 and 14-24 and 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.
Regarding claim 2, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims dependent on claim 2 are also rejected because the depend on claim 2.
Claim 9 recites the limitation "the active X-linked allele" in line 1. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim 9 is 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 9 refers to an active X-linked allele is associated with an X-linked disorder, however, claim 9 depends on claim 2 and claim 2 does not recite an active X-linked allele and preferably limits the cell to a female heterozygous or male hemizygous.. A cell from an individual having an inactivating X-linked allele is hemizygous for most genes located on the X chromosome that do not have a corresponding copy on the Y chromosome. 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-5, 8-10, and 14-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10961532, cited on an IDS in view of US 9737493. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a method of activating an X-linked allele in a cell comprising administering to the cell a DNMT inhibitor and an inhibitory nucleic acid targeting XIST RNA. The only difference is the instant claims limit the DNMT inhibitor to RG108 or decitabine.
However, RG108 and decitabine are well-known DNMT inhibitors as taught by ‘493 (column 10) and could be used in the method with a reasonable expectation of success.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the claims of 532 with teaching of taken of ‘493, namely to arrive at the claimed invention. It would have been obvious as a simple substitution to use either RG108 or decitabine as taught by ‘493 as the DNMT inhibitor in the claims of ‘994.
Claim 2 of ‘532 recites the limitations of instant claim 3. Claim 5 of ‘532 recites the limitations of instant claim 10.
The structural limitation of the inhibitory nucleic acid targeting XIST RNA recited in dependent claims 14-24 are recited in claims 2-18 of ‘532. Thus, the structural limitations recited in the instant claims would have been an obvious variant of the claims of ‘532.
In addition, when one of ordinary skill in the looks for what inhibitor is embraced by the term ‘DNMT inhibitor’, they would look at the disclosure of ‘994 and reasonably determine that either inhibitor is embraced by the term. “The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim.” See MPEP 804(II)(B)(1).
Claims 1 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11912994 in view of US 9737493. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a composition comprising a DNMT inhibitor and an inhibitory nucleic acid targeting XIST RNA. The only difference is the instant claims limit the DNMT inhibitor to RG108 or decitabine.
However, RG108 and decitabine are well-known DNMT inhibitors as taught by ‘493 (column 10) and could be used in the method with a reasonable expectation of success.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the claims of 532 with teaching of taken of ‘493, namely to arrive at the claimed invention. It would have been obvious as a simple substitution to use either RG108 or decitabine as taught by ‘493 as the DNMT inhibitor in the claims of ‘994.
In addition, when one of ordinary skill in the looks for what inhibitor is embraced by the term ‘DNMT inhibitor’, they would look at the disclosure of ‘994 and reasonably determine that either inhibitor is embraced by the term. See MPEP 804(II)(B)(1).”
Conclusion
See attached PTO-326 for disposition of claims.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. US 20170044609 and US 20160313304 (cited on an IDS) both disclose a method of reactivating expression of at least one Xist-dependent silenced X chromosome gene or a silenced Xist-dependent autosome gene comprising: a molecule that disrupts or prohibits an Xist long noncoding RNA interaction and inhibiting DNA methylation, but appear to have an effective filing date 4/24/15 after the filing date (4/7/15) of the instant application.
The closest prior art is Bhatanagar (PNAS 2014, 111:12591-12598) taken with Lee (WO2014025887), both cited on an IDS.
Bhatnagar et al. teach a RNA interference screen identified new trans-acting factors that are required for mammalian X-chromosome inactivation (XCI). See pages 12591-12598. Chemical inhibitors of some of these factors can reversibly reactivate the inactive X chromosome. The results showing reactivation of the silenced wild-type MECP2 allele have therapeutic implications for Rett syndrome. The results of Figures 3A and B implied that Xist was also necessary for maintenance of XCI. Xist antisense LNA oligonucleotide perturbed the normal pattern of Xist expression/localization (Fig 3C). The oligonucleotide increased biallelic expression of Mecp2. DNMT is an activator of Xist transcription. Knockdown of DNMT in fibroblasts or murine ES cells decreased Xist expression but did not affect Tsix levels. Small molecule XCIF inhibitors could reactivate an Xi-linked wild-type Mecp2 allele in clonal fibroblast from an RTT patient
Lee teaches a method of reactivating mecp2 on an inactive X chromosome. (pages 55 and 449-452). An inhibitory nucleic acid targeting XIST RNA can be used
Neither Bhatnagar nor Lee teach or suggest combining a nucleic acid targeting XIST RNA with a DNMT inhibitor.
In view of the totality of the prior art of record, one of ordinary skill in the art would conclude based on the findings of Bhatanagar that the two inhibitors function to inhibit the same pathway and would not have concluded that there would be an additive effect when using both. This is further supported by the contradictory findings in the prior art regarding the role of XIST RNA in transcriptional repression inactive genes on Xi (see Wutz and Jaenisch Molec Cell 5: 695-705, 2000, of record). One of ordinary skill in the art would be aware of these conflicting findings and would not have been motivated to combine an inhibitory nucleic acid that targets XIST RNA with a DNMT inhibitor to reactivate an allele on the inactive Xi let alone with a reasonable expectation of success. In addition, Example 5 (Figures 8a and 8b) and Table 11 of the as-filed specification demonstrate more than additive effect on gene reactivation on the Xi using the claimed combination which is considered an unexpected result and this result also overcomes any 103 rejection, including a rejection based on Bhatanagar and Lee.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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