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 .
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.
Claim Status
Applicant’s arguments and amendments dated 3/3/26 have been received and entered in the application.
Claims 1-2, 5-8, 11-12, 15, 17, 20, 24, 27, 34-35, 38-45 are currently pending and examined on the merits.
Claims 1, 6-715, 17, 34-35, 38-41 are currently amended.
Claim 45 is newly added.
Claim Rejections - 35 USC § 112(a)/1st paragraph
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.
Enablement
Claims 6-8, 38-45 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 enablement requirement. The specification, while being enabling for multiplying bovine embryos, does not reasonably provide enablement for multiplying embryos from other species. The specification contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.” See MPEP § 2164. These factors 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;
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(A) With respect to the breadth of the claims, the claims as currently drafted encompass methods of multiplying donor embryos. The instant claims limit the methods to ruminant animals.
(B) The invention is in the field of serial embryo splitting.
(C)-(E) With respect to the state of the prior art, and predictability of the art, success in embryo splitting is species-specific. Casser et al., (2019) Multiplying embryos: experimental monozygotic polyembryony in mammals and its uses. Int. J. Dev. Biol., 63: pp. 143-155 (hereinafter Casser)., discloses that the preferable stage of bisection and success rate is species specific (Introduction, Stage of embryo bisection matters: lessons from sheep, cattle and other mammalian species). In particular, sheep embryo quality and viability depend on the embryonic stage at which bisection is performed. Bovine embryos split at the 2-cell stage, in the morula, or in the blastocyst do not significantly vary in quality or viability (Stage of embryo bisection matters: lessons from sheep, cattle and other mammalian species). Therefore, embryo splitting in ruminant species is an art with a degree of unpredictability.
(F)-(G) The applicants have provided multiple working examples directed to splitting of bovine embryos. The applicants have not provided working examples for any other ruminant species.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the breadth of the claims, the state of the prior art and its lack of predictability, and the limited amount of guidance in the form of varied working examples in the specification.
MPEP §2164.01(a), 4th paragraph, provides that, “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 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 6-8, 38-45, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in claims 6-8, 38-45 would not be enabled by the written disclosure. Therefore, claims 6-8, 38-44 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate with the claims as presented.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 5, 11-12, 15, 17, 20, 24, 27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Silvestri, G. (2017) Novel approaches of generating and selecting high genetic merit in vitro produced pig and cattle embryos. Thesis, University of Kent (hereinafter Silvestri).
Regarding claims 1-2, 5, 17, Silvestri compares methods for splitting embryos to increase offspring (Abstract). Silvestri discloses that embryos may be serially split; an embryo may be split from an embryo derived from a previous split (1.4.2.9). Silvestri discloses serial splitting bovine embryos using three different strategies. In the first strategy, eight-cell stage embryos are split into two 4/8 splits (2.2.3.4, 4.4.6, 4.4.6.1, Fig. 2.5). Embryos that progress to form a blastocyst are split a second time via bisectioning (2.2.3.4, 4.4.6,4.4.6.1, Fig. 2.5). For the second strategy, two-cell stage embryos are split via disaggregation (2.2.3.5, 4.4.6). Embryos that demonstrate cleavage are disaggregated a second time (2.2.3.5, 4.4.6, 4.4.6.2). For the third strategy, embryos are disaggregated a third time to form third serial splits (2.2.3.5, 4.4.6, 4.4.6.2). Silvestri explains that triple embryo splitting results in a decrease in blastulation rate of the splits, but produces an increase in the net output of blastocysts (4.5.5).
Regarding claims 11-12, Silvestri discloses that the embryos are subjected to enzymatic digestion or mechanical removal of the zona pelucida (ZP) followed by separation of the blastomere (1.4.2.1, Fig. 1.17). Silvestri explains that splitting at the cleavage stage embryo is that it can lead to the formation of a number of embryos equal to the number of blastomeres recovered (1.4.2.1). Alternatively, a blastocyst may be bisectioned by passing a fine bore pipette through an embryo to produce two demi-embryos (1.4.2.2, Fig. 1.18).
Regarding claim 15, the embryos are cultured in synthetic ovarian fluids amino acids citrate inositol supplemented with fetal bovine serum, bovine serum albumin, and antibiotics (2.2.2.5).
Regarding claim 20, Silvestri discloses that bovine embryos are produced by in vitro fertilization (2.2.2, 2.2.2.3-2.2.2.4).
Regarding claim 24, Silvestri discloses that embryos may be biopsied for preimplantation genetic diagnosis, genetic screening, or genomic selection (1.6, 1.7, 1.9, Fig. 1.22).
Therefore, every limitation of claims 1, 5, 11-12, 15, 17, 20, 24, 27 is present in Silvestri, and the subject matter is anticipated.
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.
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.
Claim(s) 1, 5, 11, 12, 15, 17, 20, 24, 27, 34-35, is/are rejected under 35 U.S.C. 103 as being unpatentable over Silvestri as applied to claims 1, 5, 11-12, 15, 17, 20, 24, 27 above, in view of Rho et al., (1998) Cellular composition and viability of demi- and quarter-embryos made from bisected bovine morulae and blastocysts produced in vitro. Theriogenology, 50: pp. 885-895 (hereinafter Rho).
Regarding claims 34-35, Silvestri does not disclose that the resultant embryo is transferred to a female recipient to produce an animal via parturition.
Rho compares methods of bovine embryo splitting, including serial splitting (Abstract). Rho discloses mechanically bisecting a blastocyst with a microsurgical blade (Bisection and quality classification of embryos). In some embodiments, following 24 hours of culture, the demi-embryos are bisected a second time to produce quarter-embryos (Bisection and quality classification of embryos). Rho explains that serial bisection produced a similar quantity of transferable embryos to embryos bisected a single time (Discussion). Rho further discloses transferring quarter-embryos to heifers in estrus with pregnancy confirmed by transrectal ultrasonography (Transfer of quarter-embryos).
Rho does not disclose obtaining an animal via parturition. However, Rho discloses that at 90 days post-transplantation fetus and fetal membranes appeared normal (Results). Rho suggests that the disclosed methods could be successfully utilized for production of live calves (Discussion). Therefore, there is a suggestion present in Rho that the disclosed methods may be used to successfully produce live animals.
As both Silvestri and Rho are directed to methods of splitting embryos, in particularly serial splitting, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to combine the references for the successful production of multiple live birth calves from a single embryo.
Claim(s) 6-8, 38-45, is/are rejected under 35 U.S.C. 103 as being unpatentable over Rho in view of Silvestri.
Regarding claims 6-7, 38-39, 41, 45, Rho compares methods of bovine embryo splitting, including serial splitting (Abstract). Rho discloses mechanically bisecting a blastocyst with a microsurgical blade (Bisection and quality classification of embryos). In some embodiments, following 24 hours of culture, the demi-embryos are bisected a second time to produce quarter-embryos (Bisection and quality classification of embryos). Rho explains that serial bisection produced a similar quantity of transferable embryos to embryos bisected a single time (Discussion).
Regarding claim 40, embryos are cultured in M199 media containing Earle’s salts supplemented with sodium pyruvate, glutamine, antibiotics, and polyvinyl alcohol (Media).
Regarding claim 42, Rho discloses producing bovine morulae and blastocytes by in vitro fertilization (Embryo preparation).
Regarding claims 6, 45, Rho does not disclose disrupting the zona pellucida using non-mechanical means. Regarding claim 8, Rho does not disclose that the embryos are serially split at least two times. Regarding claim 43, Rho does not disclose that the embryos are selected base on genetic criteria.
Silvestri compares methods for splitting embryos to increase offspring (Abstract). Silvestri discloses that embryos may be serially split; an embryo may be split from an embryo derived from a previous split (1.4.2.9). Silvestri discloses serial splitting bovine embryos using three different strategies. In the first strategy, eight-cell stage embryos are split into two 4/8 splits (2.2.3.4, 4.4.6, 4.4.6.1, Fig. 2.5). Embryos that progress to form a blastocyst are split a second time via bisectioning (2.2.3.4, 4.4.6,4.4.6.1, Fig. 2.5). For the second strategy, two-cell stage embryos are split via disaggregation (2.2.3.5, 4.4.6). Embryos that demonstrate cleavage are disaggregated a second time (2.2.3.5, 4.4.6, 4.4.6.2). For the third strategy, embryos are disaggregated a third time to form third serial splits (2.2.3.5, 4.4.6, 4.4.6.2). Silvestri explains that triple embryo splitting results in a decrease in blastulation rate of the splits, but produces an increase in the net output of blastocysts (4.5.5).
Silvestri discloses that the embryos are subjected to enzymatic digestion or mechanical removal of the zona pelucida (ZP) followed by separation of the blastomere (1.4.2.1, Fig. 1.17). Silvestri explains that splitting at the cleavage stage embryo is that it can lead to the formation of a number of embryos equal to the number of blastomeres recovered (1.4.2.1). Alternatively, a blastocyst may be bisectioned by passing a fine bore pipette through an embryo to produce two demi-embryos (1.4.2.2, Fig. 1.18).
Silvestri further discloses that embryos may be biopsied for preimplantation genetic diagnosis, genetic screening, or genomic selection prior to splitting (1.6, 1.7, 1.9, Fig. 1.22).
As both Silvestri and Rho are directed to methods of splitting embryos, in particularly serial splitting, it would be obvious to one of ordinary skill in the art that the references could be combined. Regarding claims 6, 45, a skilled artisan would understand that the non-mechanical means could be used to disrupt the zona pellucida as Silvestri teaches that mechanical removal and enzymatic digestion are art recognized alternatives. Regarding claim 8, a skilled artisan would be motivated to combine the references for the successful production of multiple, optimized monozygotic embryos as taught by Rho. Regarding claim 43, a skilled artisan would be motivated to select embryos based on genetic criteria as application of a known technique to improve a similar method in the same way.
Response to Arguments
Applicant's arguments dated 3/3/26 have been fully considered but are moot in part and not persuasive in part due to the new grounds of rejection necessitated by applicant’s amendments. To the extent that the arguments are pertinent to the current grounds of rejection they are responded to below.
Claims 6-8, 38-45 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 enablement requirement.
Applicant argues that early reproductive and embryonic biology is conserved among ruminant livestock species (Response p10). Applicants point to Bazer as demonstrating that ruminant species undergo comparable pre-implantation development (Response p10).
In response, applicants have not provided a copy of the Bazer reference. Applicants assertions with respect to Bazer cannot be verified. Further, the Casser reference cited in the rejection under 35 U.S.C. 112(a) directly contradicts applicants arguments. Casser discloses that different ruminant species respond to bisection differently; sheep embryo quality and viability depend on the embryonic stage at which bisection is performed, bovine embryos do not significantly vary in quality or viability at different stages for bisection. Therefore, applicants arguments are not considered persuasive.
Claim(s) 1, 5, 11-12, 15, 17, 20, 24, 27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Silvestri.
Applicant argues that claim 1 has been amended to require at least four serial rounds of splitting such that Silvestri no longer anticipates the claim (Response p11).
Claim 1 has not been amended and requires no more than 3 rounds of serial splitting. Therefore, Silvestri anticipates the claims as presented.
Claim(s) 1, 5, 11, 12, 15, 17, 20, 24, 27, 34-35, is/are rejected under 35 U.S.C. 103 as being unpatentable over Silvestri in view of Rho.
Applicant argues that claim 1 has been amended to require at least four serial rounds of splitting such that Silvestri no longer anticipates the claim (Response p14).
As noted above, claim 1 was not amended and applicant’s arguments do not pertain to the current claims.
Claim(s) 6-8, 38-45, is/are rejected under 35 U.S.C. 103 as being unpatentable over Rho in view of Silvestri.
Applicant argues that Silvestri teaches away from using enzymatic disaggregation to disrupt the zona pellucida of embryos at the 16 cell or pre-compacted morula stage (Response p16-17).
In response, disclosed examples and preferred embodiments do not constitute a teaching away. To constitute a teaching away the reference must criticize, discredit, or otherwise discourage the solution claimed. See MPEP §§ 2123, 2143.01. Silvestri explicitly discloses that the zona pelucida may be enzymatically disaggregated. As noted in the art rejections supra, Silvestri teaches that mechanical removal and enzymatic digestion are art recognized alternatives used for the same purpose. Therefore, Silvestri does not qualify as a teaching away.
Applicant argues that there is no motivation to combine or modify Rho, and there is no expectation of success even if the combination is made (Response p16-18). Applicant argues that the lack of success experienced by Silvestri when performing the protocol taught in Rho demonstrates the general unpredictability such that a skilled artisan would not have been motivated to combine the references (Response p17-18).
In response, Silvestri does not disclose replicating the methods of Rho; Silvestri states that “a similar application” was unsuccessful (emphasis added). Silvestri further states that serial splitting holds the promise to dramatically increase the availability of blastocysts for transfer and suggests additional research. Rho likewise states that embryo splitting can be a useful tool for increasing the production of transferable embryos. Therefore, there is motivation found in each of the references for further modifications. As to the specific rationales for combining they are recited in the art rejections above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
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/KARA D JOHNSON/ Primary Examiner, Art Unit 1632
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