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 .
Claims 1-8 and 10-14 are pending in the application. Claims 10-14 are withdrawn. Claims 1-8 and 10 are currently under examination.
This office action is in response to the amendment filed on 11/26/2025.
All previous rejection not reiterated in this office action are withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: how to increase the rate of genetic progress in the non-human mammalian species by performing the method steps. The method ends with a selecting step wherein the second embryo is selected based on EBV or genotypic value. However, it is unclear how such selection will increase rate of genetic progress as claimed.
Claims 2-4 are rejected for same reason because they depend on claim 1 and do not provide additional steps to accomplish this purpose.
Response to Arguments
Applicant argues that the specification explains a step of “selection” based on genetic merit can yield an increase in the rate of genetic progress as set forth in 2nd paragraph on page 7. Applicant asserts that the term “genotypic value” is expressly defined in the specification at page 8 to mean “an individual’s breeding value plus non-additive genetic effects, such as dominance and epistasis.” Applicant asserts that one of ordinary skilled in the art would understand that in the context of the claimed invention, “selecting a first embryo from the plurality of embryos based on an estimated breeding value or genotypic value of the first embryo” means the first embryo’s breeding value is higher than the average breeding value of the plurality of embryos from which it is selected.
The above argument has been fully considered but deemed unpersuasive. The 112 b statue requires a claim must be complete by itself. The description how desirable genetic change can be measured resulting from the selection process (on page 8, 1st paragraph) is essential subject matter for the claimed invention for the purpose of increasing the rate of genetic progress in a non-human mammalian species. However, the claim does not recite any steps that directs to increasing the rate of genetic progress. The definition of “genotypic value” being used as a selection criteria does not equate to “increasing the rate of genetic progress” as recited. Therefore, this rejection is still considered proper and thus maintained.
Claims 1-8 and 10 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 of increasing rate of genetic progress in a mouse comprising genotyping a plurality of embryos of the mouse; selecting a first embryo from the plurality of embryo from the plurality of the embryos based on estimated breeding value (EBV) or genotypic value of the first embryo; obtaining a plurality of cells from the first embryo; transfer the plurality of cells’ nuclei into a plurality of enucleated eggs to produce a plurality of nuclear transfer eggs via haploidization; fertilizing the plurality of nuclear transfer eggs with sperm cells to produce a second plurality of embryos; genotyping the second plurality of embryos; and selecting a second embryo from the second plurality of embryos based on an EBV or genotypic value of the second embryo, does not reasonably provide enablement for the claimed method in other non-human mammalian species. 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/use the invention commensurate in scope with these claims. This is a new ground of rejection necessitated by amendment.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claims are drawn to a method of increasing the rate of genetic progress in a non-human mammalian species or a method of generating a line in a non-human mammalian species comprising selecting a first embryo from the plurality of embryo from the plurality of the embryos based on estimated breeding value (EBV) or genotypic value of the first embryo; obtaining a plurality of cells from the first embryo; transfer the plurality of cells’ nuclei into a plurality of enucleated eggs to produce a plurality of nuclear transfer eggs via haploidization; fertilizing the plurality of nuclear transfer eggs with sperm cells to produce a second plurality of embryos; genotyping the second plurality of embryos; and selecting a second embryo from the second plurality of embryos based on an EBV or genotypic value of the second embryo.
The breadth of the claim
The claim scope of claim 1 and claim 5 encompasses such a method in a wide variety of non-human mammalian species.
The teaching from the specification and the presence of working examples
With regard to the claimed method of claim 1 and claim 5, the specification on page 3 and 4 describes the claimed method being one of the embodiment of the invention. The specification teaches one aspect of the invention encompasses the use of “pseudo eggs” generated using haploidization, citing Lee’s 2022 publication titled “Haploidy in somatic cells is induced by mature oocytes in mice. The specification teaches any haploidization protocol may be used including Lee et al., Palermo and Tesarik et al. The specification teaches “using the process of haploidization described by those authors the replacement of meiotic spindles in a mature or immature oocytes with the nucleus of one of the aforementioned donor cell types results in the formation of de novo spindles consisting of donor cell homologous chromosomes comprised of single chromatids.” The specification does not provide any working examples for carrying out the claimed method. As such, a skilled artisan would rely on prior art known method to practice the claimed method, especially the step of nuclear transfer of enucleated eggs via haploidization.
The state of prior art and the level of predictability in the art
The state of art at the time of filing has very limited success regarding nuclear transfer eggs via haploidization. In a review article by Lee and Kang (J Anim Reprod Biotechnol 2022; 37: 213-217), the authors states “until now, several investigators have attempted somatic haploidization. Tu induce haploidization of the diploid somatic genome, somatic cells were transferred into enucleated oocytes. However, earlier studies have shown abnormal separation and alignment processes in reconstructed chromosomes and limited development of the preimplantation embryos (Palermo et al). One research group induced somatic haploidization in the reconstructed oocytes by fertilization using spermatozoon in humans, resulting in the segregation of homologous chromosomes shown in only several chromosomes, and the embryo was not developed (Tesarik et al., 2001). Recently, one study tried somatic haploidization using somatic cell nuclear transfer with fertilization in mice (Lee et al., 2022). This study demonstrated that the somatic homologous chromosomes were segregated into blastocysts carrying somatic genomes and produced offspring.”(page 21, 2nd col., bridging paragraph to page 214, 1st col., and 2nd paragraph of 1st col on page 214). Based on above teaching, there is only one publication, Lee et al., which produced live offspring in mice with the technology of nuclear transfer to eggs via haploidization at the time this application was filed. As such, whether the claimed method that involves a step of nuclear transfer to eggs via haploidization may apply to other non-human mammalian species including bovids (claim 4 and 7) is unpredictable.
The amount of experimentation required
Due to lack of teaching from the specification and limited teaching from prior art, a skilled artisan would have to engage in undue experimentation to practice the method that comprises the step of nuclear transfer a cell’s nucleus into an enucleated egg to produce a nuclear transfer egg via haploidization in other mammalian non-human species besides mouse. Therefore, the claimed method is only enabled to the scope as indicated above.
Priority
The present application is a CIP of co-pending application 16/195,552, which has a filing date of 11/19/2018. However, since the amendment introduces a new limitation regarding nuclear transfer egg via haploidization, which was not disclosed in the prior filed ‘552 application, the priority date of the present application is the filing date of present application 5/13/2022.
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.
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.
Claim(s) 1-3, 5-6, 8 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Campbell (cited previously), in view of Lee et al (IDS). This is a new rejection necessitated by amendment.
Regarding claim 1, Campbell teaches a method for producing an offspring of an animal by nuclear transfer, using donor genetic material in cells taken from an animal including embryo (page 1, 1st paragraph). Campbell teaches the process may be used to introduce genetic modification into the resultant offspring by genetic manipulation and selection of the cells to act as nuclear donors prior to embryo reconstruction (page 1, 1st paragraph). Campbell teaches this process may be repeated to produce animals containing multiple genetic modifications (page 1, 1st paragraph). Campbell teaches that the recipient cell is preferably an enucleated oocyte (egg) (page 5, last paragraph, and page 6, 2nd paragraph). Campbell teaches transferred oocyte needs to be activated for further development by various means including with sperm (page 8, 1st paragraph). Campell teaches two consecutive nuclear transfer procedure before the final transfer to a surrogate for development of the animal to term (page 9-10, bridging paragraph). Campbell teaches the genetic material can be modified at any stage in the double nuclear transfer methodology, either before the first nuclear transfer step or in between the first and second nuclear transfer steps (page 19, 2nd paragraph). The present specification defines “genotypic value” encompasses an individual’s breeding value plus non-additive genetic effects. As such, selecting an embryo based on such “genotypic value” encompasses determining whether the embryo comprises the genetic modification. The teaching from Campbell inherently comprises genotyping embryo and making selection based on genotypic value because an ordinary skilled in the art would have to determine whether the starting genetic material from donor and resultant genetic material of the recipient to know whether the genetic modification has been introduced. Campbell teaches the method is applicable to mouse (page 3, line 28).
However, Campbell does not teach the step of nuclear transfer eggs via haploidization.
Lee et al. teaches the replacement of meiotic spindles in mature metaphase II arrested oocytes with nuclei of somatic cells in G0/G1 stage of cell cycle results in formation of de novo spindles consisting of somatic homologous recombination comprising single chromatids in mouse cells, and fertilization of such oocytes with sperm triggers the extrusion of one set for homologous chromosomes into the pseudo-polar body resulting a zygote with haploid somatic and sperm pronuclei (abstract).
It would have been obvious to an ordinary skilled in the art at the time of filing to recognize that transferring nuclei to enucleated eggs via haploidization and subsequence fertilization the transferred egg with sperm taught by Lee et al. may be an alternative to the nuclear transfer method taught by Campbell based on combined teaching from Campell and Lee et al. Since Lee demonstrates the successful generation of haploid egg by chromosome segregation following somatic nuclear transfer in a mouse model, the ordinary skilled in the art would have reasonable expectation of success to apply said method in the double nuclear transfer method for making genetic modification into the resultant offspring by genetic manipulation and selection of the cells to act as nuclear donors prior to embryo reconstruction. Therefore, the claimed invention would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 2, Campbell teaches the nuclear transfer process may be repeated, which involves further nuclear transfer from the first embryo (page 1, 1st paragraph).
Regarding claim 3, Lee teaches both female MEFs (mouse embryonic fibroblast) and adult fibroblast isolated from mouse embryo and ear skin were used as donor cell for SCNT (page 12, 2nd col., 5th paragraph).
Regarding claim 5, Lee teaches BDF1 donors fertilized with BDF1 sperm cells yields highest number of blastocysts and in vivo production (Figure 8a-b and 8f and legend, and page 9, 1st col., 1st paragraph, and 2nd col., last paragraph). Although Lee does not teach whether they are full sibs or half sibs, it would have been obvious to an ordinary skilled in the art that they are from same strain, which means they are genetically nearly identical, sharing a fixed genotype and produced by sibling mating. It would have been obvious to an ordinary skilled in the art to use sibling mating to ensure highest number of blastocysts production that will lead to production of live offspring as demonstrated by Lee et al.
Regarding claim 6, The teaching from Campbell inherently comprises genotyping embryo and making selection based on genotypic value because an ordinary skilled in the art would have to determine whether the starting genetic material from donor and resultant genetic material of the recipient to know whether the genetic modification has been introduced.
Regarding claim 8, Lee teaches both female MEFs (mouse embryonic fibroblast) and adult fibroblast isolated from embryo and ear skin were used as donor cell for SCNT (page 12, 2nd col., 5th paragraph).
Regarding claim 10, Campbell teaches the nuclear transfer process may be repeated, which involves further nuclear transfer from the first embryo (page 1, 1st paragraph).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637