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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
Previous rejections are maintained and all arguments are addressed at the end of the office action.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-5 and 16 remain rejected under 35 U.S.C. 103 as being unpatentable over US 11,390,885 (paragraph numbers are cited from USPGPUB 2017/0327846 in view of Loi (2016, Trends in Biotechnology. 34:791-797; IDS).
Claim 1 is drawn to a method for obtaining a blastocyst comprising transferring a donor nucleus form a somatic cell lacking Xist activity into and enucleated oocyte and expressing Kdm4d in the oocyte.
Regarding Claim 1, ‘885 discloses a method for obtaining a cloned blastocyst comprising generating a somatic cell nuclear transfer (SCNT)-embryo using the nucleus of a donor embryonic fibroblast) and obtaining a blastocyst from the SCNT embryo (see para 405). ‘846 teaches increasing the efficiency of SCNT comprising contacting the recipient oocyte with a Kdm4 histone demethylase (expressing in the oocyte Kdm4d, as claimed; see para 24) by introducing a mRNA encoding Kdm4d, as recited by claim 2 (see paragraph 25, 523). Embryos at the 2-cell stage were transferred into the oviducts for gestation, which leads to implantation in the uterus (see para 531), meeting the limitations of claim 5. With regard to the limitation of previous claim 6, that is now part of claim 1, ‘885 teaches that 7.6% of Kdm4d-injected embryos developed to term (live birth) whereas none of the 104 control embryos did. Similarly, ‘846 taught when using Sertoli cells as donors, 1% of pups make it to term without the use of Kdm4 overexpression in the oocyte. Addition of Kdm4 overexpression leads to 8.7% live birth rate.
With regard to claim 4, at paragraph 569, ‘885 teaches that other species of animals have a similar developmental defect of SCNT concurrent with ZGA (zygotic gene activation) including human, pig, bovine and rabbit and the reprogramming barrier is likely to be conserved. ‘885 states “Accordingly, Kdm4d mRNA injection can be used to enhance and improve the cloning efficiency in a broad range of mammals, including humans and domestic animals.” (see para 569; see also para 38,44).
Thus, ‘885 meets all of the limitations of claim 1-5 with exception of the requirement in claim 1 that the donor nucleus come from a somatic cell lacking Xist activity. It is noted that ‘885 teaches that in addition to demethylating RRRs to remove the block to reprogramming by expression of Kdm4d (a demethylase), histone methyltransferase can also be inhibited to prevent methylation (e.g. siRNA inhibition of Suv39h1).
However, Loi taught that it was a major breakthrough in SCNT with the understanding that Xist knockout or knockdown remarkably increased the birthrates of cloned mice. Following this finding, it was discovered that it was histone H3 lysine 9 trimethylation that was the major barrier to nuclear reprogramming and ectopically expressing Kdm4d (a demethylase) was another, independent approach to overcoming the reprogramming barrier and enabling genes in the RRR to be transcribed. Interestingly, it was also found that another advance in the efficiency of SCNT, use of Trichostatin A (a histone deacetylase inhibitor) activated the same genes in the RRR as Kdm4d expression and Xist inhibition. Loi states, “Thus, now we understand that H3K9me3 and Xist are the major targets for improvements in SCNT efficiency.” With regard to claim 16, Loi teaches that Xist activity had been removed by both gene knockout (genome editing, as claimed) and by RNA interference (RNAi). See page 793. With regard to H3K9me3 ablation, and Xist downregulation, Loi teaches that it would be “… be logical to expect further improvement from the synergy of these treatments” (See Discussion).
It would have been obvious to one of ordinary skill in the art at the time of the invention to combine the method of ‘885 to include repression of Xist by Xist gene removal from the donor as taught by Loi to arrive at the invention as claimed. One would have been motivated to make such a combination because Xist was shown to be aberrantly expressed in poorly developing SCNT embryos and its expression was associated histone methylation reduction, which is also an effect of Kdm4d expression. As well, Loi taught that it is logical to expect further improvement from the synergy of the treatments. One would have had a reasonable expectation of success in making the combination as all requisite technologies were within the realm of the knowledge of the person of ordinary skill in the art and each technology was found to have a positive effect on development by the removal of RRR regions through demethylation.
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 1-5 and 16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,4,7,8 of U.S. Patent No. 10,266,848 (IDS) in view of Loi (Trends in Biotechnology, 2016,34:791-797).
Claim 1 is drawn to a method for obtaining a blastocyst comprising transferring a donor nucleus form a somatic cell lacking Xist activity into and enucleated oocyte and expressing Kdm4d in the oocyte. Claim 2 limits the Kdm4d to an mRNA. Claim 3 limits the lack of Xist to deletion of Xist or an inactive Xist form. Claim 4 limits the species of animal. Claim 5 limits the method to include blastocyst transfer.
The ‘848 claims are directed to methods for increasing the efficiency of mammalian somatic nuclear transfer (SCNT) comprising injecting an enucleated mammalian oocyte comprising a donor nucleus of the same species with a Kdm4 mRNA (claim 1). Claim 4 requires blastocyst transfer. Claim, 7 limits the species of mammal and Claim 8 limits the degree of increase efficiency. ‘848 does not teach the lack of Xist activity.
It is noted that ‘848 teaches that in addition to demethylating RRRs to remove the block to reprogramming by expression of Kdm4d (a demethylase), histone methyltransferase can also be inhibited to prevent methylation (e.g. siRNA inhibition of Suv39h1). Additionally, Loi taught that it was a major breakthrough in SCNT with the understanding that Xist knockout or knockdown remarkably increased the birthrates of cloned mice. Following this finding, it was discovered that it was histone H3 lysine 9 trimethylation that was the major barrier to nuclear reprogramming and ectopically expressing Kdm4d (a demethylase) was another approach to overcoming the reprogramming barrier and enabling genes in the RRR to be transcribed. Interestingly, it was also found that another advance in the efficiency of SCNT, use of Trichostatin A (a histone deacetylase inhibitor) activated the same genes in the RRR as Kdm4d expression and Xist inhibition. Loi states, “Thus, now we understand that H3K9me3 and Xist are the major targets for improvements in SCNT efficiency.”
It would have been obvious to one of ordinary skill in the art at the time of the invention to combine the method of ‘848 to include repression of Xist by Xist gene removal from the donor as taught by Loi to arrive at the invention as claimed. One would have been motivated to make such a combination because Xist was shown to be aberrantly expressed in poorly developing SCNT embryos and its expression was associated histone methylation reduction, which is also an effect of Kdm4d expression. As well, Loi taught that it is logical to expect further improvement from the synergy of the treatments. One would have had a reasonable expectation of success in making the combination as all requisite technologies were within the realm of the knowledge of the person of ordinary skill in the art and each technology was found to have a positive effect on development by the removal of RRR regions through demethylation. Accordingly, the instant claims are rendered obvious by the ‘848 claims because the ‘848 claims recite methods of introducing a Kdm4d a mammalian oocyte a method of SCNT and Loi teaches the addition of Xist removal to synergistically increase SCNT efficiency.
Claims 1-5 and 16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3-8 of U.S. Patent No. 11,390,885 in view of Loi (Trends in Biotechnology, 2016,34:791-797).
Claim 1 is drawn to a method for obtaining a blastocyst comprising transferring a donor nucleus form a somatic cell lacking Xist activity into and enucleated oocyte and expressing Kdm4d in the oocyte. Claim 2 limits the Kdm4d to an mRNA. Claim 3 limits the lack of Xist to deletion of Xist or an inactive Xist form. Claim 4 limits the species of animal. Claim 5 limits the method to include blastocyst transfer.
The ‘885 claims are directed to a composition comprising a non-human mammalian somatic nuclear transfer (SCNT) embryo comprising a nucleus obtained from a terminally differentiated donor somatic cell and Kdm4 mRNA (claim 1). ‘885 does not teach the lack of Xist activity.
It is noted that ‘885 teaches that in addition to demethylating RRRs to remove the block to reprogramming by expression of Kdm4d (a demethylase), histone methyltransferase can also be inhibited to prevent methylation (e.g. siRNA inhibition of Suv39h1). Additionally, Loi taught that it was a major breakthrough in SCNT with the understanding that Xist knockout or knockdown (deletion, siRNA etc; claim 16) remarkably increased the birthrates of cloned mice. Following this finding, it was discovered that it was histone H3 lysine 9 trimethylation that was the major barrier to nuclear reprogramming and ectopically expressing Kdm4d (a demethylase) was another approach to overcoming the reprogramming barrier and enabling genes in the RRR to be transcribed. Interestingly, it was also found that another advance in the efficiency of SCNT, use of Trichostatin A (a histone deacetylase inhibitor) activated the same genes in the RRR as Kdm4d expression and Xist inhibition. Loi states, “Thus, now we understand that H3K9me3 and Xist are the major targets for improvements in SCNT efficiency.”
It would have been obvious to one of ordinary skill in the art at the time of the invention to combine the method of Loi with the SCNT embryo of ‘885 to include repression of Xist by Xist gene removal from the donor as taught by Loi to arrive at the invention as claimed. One would have been motivated to make such a combination because Xist was shown to be aberrantly expressed in poorly developing SCNT embryos and its expression was associated histone methylation reduction, which is also an effect of Kdm4d expression. As well, Loi taught that it is logical to expect further improvement from the synergy of the treatments. One would have had a reasonable expectation of success in making the combination as all requisite technologies were within the realm of the knowledge of the person of ordinary skill in the art and each technology was found to have a positive effect on development by the removal of RRR regions through demethylation.
Accordingly, the instant claims are rendered obvious by the ‘885 claims.
Applicant’s arguments relate to each of the above rejections and are addressed together.
Applicant argues that the claims have been amended to specify that the claimed donor mammalian somatic cell from which the donor nucleus is derived comprises an Xist knockout. This argument is not persuasive as the claims were already limited in that manner and this amended was previously addressed.
Applicant also argues that the ‘885 patent states that neither Xist knockdown nor knockout increases SCNT efficiency enough to be useful. This argument is not persuasive as the claims fail to require any specific degree of improved efficiency. The Loi reference, teaching donor cell Xist knockout, references Inoue, who teaches an increased efficiency from 16% to 15.4% (see Inoue, 2010, Figure 3).
Applicant argues that Loi teaches, at page 792, that only a small fraction of animals derived from SCNT develop into normal offspring (1-5%) and thus one of skill in the art would not have expected an increase in the rate of live birth from a cloned blastocyst. This argument is not persuasive. At page 793, Loi discusses that knockout of Xist led to a remarkable increase in birth rates of cloned mice (792 at para 3).
Applicant argues that Loi, in Figure 1, teaches the most relevant nuclear reprogramming strategies developed so far and does not teach Xist knockout, but does teach Xist knockdown. Applicant continues with this line of argument by referring to Matoba who teaches knockdown over knockout because knockout is irreversible. Applicant argues that the Xist knockdown of Matoba is patentably distinct from the current claims. This line of argument is not persuasive. Matoba (Xist knockdown) built upon the teachings of Inoue (Xist knockout) which were both discussed by Loi. The findings of Matoba fail to nullify the teachings of Inoue. The fact that temporary reduction of Xist by siRNA knockdown is preferred over knockout does not nullify the teachings of Inoue. A ‘better’ way of doing something does not render lesser alternatives to be nonobvious, they are just less preferred.
Applicant also presents the Zhang declarationthat states that use if a donor nucleus comprising an Xist knockout may lead to adverse consequences in the resulting embryo. This argument is not persuasive in view of the teachings of Loi who discusses the findings of Inoue that Xist knockout led to higher birthrate in SCNT. Unpredictability and adverse consequences may have been the state of the art prior to the publication of Inoue. However, Inoue (2010) reports live birth following SCNT using donor nuclei with an Xist knockout. Thus, the person of ordinary skill in the art at filing (2018) would have reasonably expected that Xist knockout would not preclude live birth.
Additionally, the relied upon Loi reference, itself references (and therefore provides the teachings of) Matoba (2011, PNAS, 108:20621-20626; of record) that teaches RNAi knockdown of Xist leads to a 12% cloning efficiency whereas controls led to a 1% efficiency. Loi, relied upon above for teaching loss of Xist, also references Matoba (2014, Cell, 159:884-895; of record), which provides the same experiments and data of the ‘858 reference. Thus, all of the requisite teachings were taught together. The references taught separate mechanisms of action and therefore, an additive effect (7.6% (cumulus nuclei) or 8.7% (Sertoli nuclei)) increase for Kdm4d overexpression and a 12% increase for Xist knockdown would yield an additive effect of 19.6-20.7% and would have been reasonably expected.
Applicant references Matoba at page 20622, col. 2, as cautioning that Xist knockout was impractical and it effects on embryo development were unclear. In response, Matoba states at page 20621 that the knockout approach is impractical because it causes irreversible modification of the donor genome and is difficult in species other than mouse. Matoba continues to state that it is unclear from the knockout studies “how and when the ectopic expression of Xist affects the development of cloned embryos”. This is not the same as teaching that the effect of Xist knockout on development is unclear. Here, Matoba is referring to an observed increase in Xist expression when SCNT is carried out.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632