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 .
Status of Claims
Claims 1-21 are canceled.
Claims 22-35 are new, are pending, and are under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/EP2022/070801, filed on 07/25/2022.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 04/05/2024, 07/25/2024, 07/30/2024, and 09/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because the it is unclear as to what line pertains to which sample; for example, the marks for TUBA vs No stain in the legend cannot be determined as unique from each other. The other samples have the same issue. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 10: “ https:/wwebacuk/Toos/msa/d ustalo/.”
Claim Interpretation
Claim 22 recites “for use in assisted reproductive technology” in the preamble. Claim 22 is directed to an in vitro method and thus the method is being interpreted as being limited to use in assisted reproductive technology. Accordingly, the recitation of “for use in assisted reproductive technology” is being given patentable weight.
Claims 28-29 are product-by-process claims. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.” Accordingly, claims 28-29 are being interpreted by the examiner according to the product itself (i.e., a non-naturally occurring human oocyte) regarding patentability.
Claims 25 and 35 recite limitations in the alternative with the use of “and/or.” The examiner is interpreting only one limitation in such a list as being required.
Claim Objections
Claims 22-27 are objected to because of the following informalities: the method claims do not recite any active step. The claims are lacking a transition phrase and thus do not contain active steps. Appropriate correction is required.
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 25, 29, and 32 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 25, 29, and 32 recite the broad recitation “at least 4- fold less than a mouse oocyte” and/or “at least 4-fold less than a HeLa cell,” and the claims also recite “at least 2-fold less than a mouse oocyte” and/or “at least 2-fold less than a HeLa cell,” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 28-29 are rejected under 35 U.S.C. 101 because:
The claimed invention is directed to a product of nature without significantly more. The claims recite a human oocyte with introduced KIFC1/HSET protein or KIFC1/HSET mRNA, wherein the introduced protein or expressed protein stabilizes the meiotic spindle, and wherein the naturally occurring human oocyte expresses the KIFC1/HSET at least 2-fold less than a mouse oocyte, at least 4-fold less than a mouse oocyte (Step 1, composition of matter). The claimed human oocyte is a product of nature exception because it is not markedly different from its naturally occurring counterpart, a human oocyte, in structure or function (Step 2A , Prong 1). This judicial exception is not integrated into a practical application because the claim is directed to the human oocyte itself, and the recited introduction of KIFC/HSET protein or mRNA does not impose any limitation that results in a markedly different human oocyte from its naturally occurring counterpart (Step 2A, prong 2). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitation of introducing naturally occurring KIFC1/HSET protein or KIFC1/HSET mRNA into a naturally occurring human oocyte merely places a naturally occurring substance into a naturally occurring cell and the limitation of differential expression as compared to a mouse oocyte also does not amount to a difference that distinguishes from the judicial exception. The claims do not require any structural modification of the oocyte, any genetic modification of the oocyte genome, or other technical feature distinguishing the claimed oocyte from a naturally occurring human oocyte. Furthermore, the recited stabilization of the meiotic spindle reflets the normal biological function of KIFC/HSET as a spindle-associated motor protein rather than a feature that distinguishes from the product of nature. Thus, when considered individually and as an ordered combination, the additional elements do not amount to significantly more than the product of nature exception (STEP 2B).
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 28-29 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). The claims are directed to a human oocyte, which reads on a human, especially when the oocyte is present in a human.
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.
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.
Claims 22-23 and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) in view of Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS), Bennabi I, et al., (EMBO Rep.;19(2):368-38, 2018, in IDS), and Hall VJ, et al., (Hum Reprod.;22(1):52-62, 2007, in IDS).
Schatten teaches introducing KIFC1/HSET protein into a human oocyte/egg for the purpose of correcting spindle defects (see title, abstract, [0018], [0041]-[0042], [0061, claim set). Schatten further teaches that the HSET introduction is not confined to cloning but extends to established “clinical ART” via ooplasmic/cytoplasmic supplementation (see [0065]-[0067]). Schatten further teaches that HSET is a mitotic kinesin that traffics to the microtubule minus ends of both meiotic and mitotic spindles, is present in the metaphase II meiotic spindle and meiotic spindle poles, and is responsible for meiotic spindle organization, see [0037] and [0101]-[0103]. Schatten additionally teaches that deficiency of HSET results in abnormal spindle formation with chromosome misalignment and aneuploid embryos, whereas restoration of HSET to spindle poles is associated with improved bipolar spindle organization; thus, HSET is a spindle-organization protein involved in maintaining proper meiotic and mitotic spindle architecture, see [0018][0027][0029][0033-0034][0036-0037][0058][0062][0101-0103].
Regarding claim 25, as a matter of claim interpretation, claim 25’s recitation of “and/or” requires only one of it disjunctive limitations to be met. The “naturally occurring” alternative is met by the human oocyte taught by Schatten prior to HSET introduction, which is naturally sourced and thus naturally occurring.
Schatten does not teach introduction of mRNA (as opposed to protein) encoding HSET; the specific greater than, or equal to, 5% bipolar probability increase; or introducing HSET at the GV/MI/MII stage.
Rawe teaches HSET’s expected association with the meiotic spindle of MII human oocytes matured in vivo, and its absence correlating with defective spindles after in vitro maturation (see results). Bennabi teaches microinjection of RNA encoding HSET into GV-arrested (prophase I) oocytes, with resulting acceleration of spindle assembly, supplying both the RNA delivery and GV/meiotic stage timing (see HSET WT and HSET N593K overexpression experiments). Hall teaches that the human oocyte HSET deficiency is correlated with spindle competence as it was not associated with the spindle in aged, failed-to-fertilize human oocytes (see discussion).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to extend Schatten’s methods of introducing HSET either directly via protein or RNA encoding HSET into human oocytes in a conventional ART context. A PHOSITA would have been motivated to do so in order to restore spindle function in HSET deficient oocytes (such as aged oocytes), thereby correcting spindle-related aneuploidy. A PHOSITA would have had a reasonable expectation of success because the art demonstrates that introducing HSET protein or RNA encoding HSET during GV/MI/MII achieves the same functional spindle effect and the resulting increase in bipolar-spindle probability is the expected, predictable outcome of correcting a documented deficiency.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) in view of Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS), Bennabi I, et al., (EMBO Rep.;19(2):368-38, 2018, in IDS), and Hall VJ, et al., (Hum Reprod.;22(1):52-62, 2007, in IDS) as applied to claim 22 above, and further in view of Mountain V, et al., (J Cell Biol. 1999 Oct 18;147(2):351-66, in IDS).
The teachings of Schatten, Rawe, Bennabi, and Hall are incorporated herein by reference to the 103 rejection above.
Schatten, Rawe, Bennabi, and Hall do not teach the HSET protein is a recombinant protein.
Mountain teaches that recombinant production of HSET was a routine, well-established technique for obtaining purified HSET protein for downstream applications (see materials and methods).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to obtain HSET protein by recombinant techniques for use in the methods of Schatten applied to ART. A PHOSITA would have been motivated in order to increase efficiency of obtaining HSET protein and to reduce costs of producing HSET protein. A PHOSITA would have had a reasonable expectation of success because recombinant protein production including HSET is a routine manufacturing choice yielding predictable results.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS) in view of Mountain V, et al., (J Cell Biol. 1999 Oct 18;147(2):351-66, in IDS).
The teachings if Rawe are incorporated herein by reference to the 103-rejection applied to claims 22-23 and 25-27 above.
Raw does not explicitly state that HSET association “stabilizes” the spindle in mechanistic terms.
Mountain teaches, via microinjection experiments, that HSET activity is essential for meiotic spindle organization, see abstract and introduction last paragraph.
It would have been obvious to a PHOSITA to recognize that the HSET-spindle association Rawe observes in naturally occurring human oocytes performs the spindle-organizing/stabilizing function Mountain established for HSET generally. A PHOSITA would have been motivated to draw this connection because both references address the same protein acting on the same structure (the oocyte meiotic spindle) in closely related mammalian systems. A PHOSITA would have had a reasonable expectation that this function applies to Rawe’s human oocytes given the established conservation of HSET’s spindle-organization mechanism across mammalian species. Because claim 28 is a product=by-process claim, the resulting product is not patentably distinguishable from Raws’s naturally occurring oocyte exhibiting the same structural feature.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS) in view of Mountain V, et al., (J Cell Biol. 1999 Oct 18;147(2):351-66, in IDS) as applied to claim 28 above, and further in view of Virant-Klun I, et al, (Mol Cell Proteomics. 2016 Aug;15(8):2616-27, in IDS, and supplemental information) and Wang S, et al., (Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17639-44, in IDS, and supplemental information).
The teachings of Raw and Mountain are incorporated herein by reference to the 103-rejection applied to claim 28 above.
Raw and Mountain to not teach that the naturally occurring human oocyte expresses the KIFC1/HSET at least 2-fold less than a mouse oocyte, at least 4-fold less than a mouse oocyte.
Virant-Klun teaches human oocyte proteomics ( and Wang teaches mouse oocyte proteomics and published the quantitative, proteome-wide datasets.
It would have been obvious to a PHOSITA to derive the relative KIF1C/HSET expression differential between the human oocyte and a mouse oocyte by comparing these two datasets. A PHOSITA would have been motivated to quantify the differential already available in the art to characterize the deficiency in fold-change in a human oocyte compared to a mouse oocyte. A PHOSITA would have had a reasonable expectation of success given the routine standardized nature of comparative proteomic analysis.
Claims 30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS).
Schatten teaches inserting a reprogrammed nucleus together with spindle-associated motor proteins including HSET, restored “in full complement,” into an actual ICSI-fertilized human zygote during interphase, [0065]. Schatten further teaches this ooplasmic/cytoplasmic supplementation technique is an established “clinical ART” method that “has succeeded already in humans,” [0067], and that missing HSET/NuMA causes multipolar spindles and aneuploid embryos, i.e., that restoring HSET lowers aneuploidy, [0058]. Schatten’s double-NT protocol expressly teaches introduction of the reprogrammed nucleus and associated spindle motor proteins, including HSET, during interphase, [0065], which encompasses S phase, one of the disjunctively-recited phases of claim 33.
It would have been obvious to a PHOSITA to apply Schatten’s HSET-restoration technique in S phase to human zygotes generally for the purpose of lowering aneuploidy probability. A PHOSITA would have been motivated to do so because Schatten itself identifies HSET deficiency as a general cause of aneuploidy following reconstruction of the zygote, independent of any SCNT-specific mechanism, and expressly extends the supplementation technique to conventional clinical ART. A PHOSITA would have had a reasonable expectation of success because Schatten demonstrates the introduction technique (microinjection/ooplasmic supplementation) is already established and successful in human cells.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) as applied to claim 30 above, and further in view of Mountain V, et al., (J Cell Biol. 1999 Oct 18;147(2):351-66, in IDS).
The teachings of Schatten are incorporated herein, namely that restoring HSET stabilizes/organizes the mitotic spindle, [0058].
Schatten does not expressly state the introduced HSET protein is recombinantly produced. Mountain teaches recombinant production of HSET was a routine, well-established technique for obtaining purified protein.
It would have been obvious to a PHOSITA to obtain Schatten’s HSET protein component via recombinant production. A PHOSITA would have been motivated to do so to increase efficiency and reduce cost of obtaining sufficient, purified HSET protein for the supplementation procedure. A PHOSITA would have had a reasonable expectation of success because recombinant protein production, including of HSET specifically, was a routine manufacturing choice yielding predictable results.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) as applied to claim 30 above, and further in view of Xue Z, et al., (Nature. 2013 Aug 29;500(7464):593-7, in IDS).
The teachings of Schatten are incorporated herein by reference to the respective 103 rejections above.
Schatten does not teach wherein the human zygote expresses KIFC1/HSET at least 2-fold less than a mouse zygote or at least 4-fold less than a mouse zygote.
Xue teaches single-cell RNA sequencing profiling of human and mouse early embryos, including the zygote stage.
It would have been obvious to a PHOSITA to derive a relative KIFC1/HSET expression comparison between human and mouse zygotes from Xue’s dataset. A PHOSITA would have been motivated to characterize, in quantitative terms, the zygote-stage HSET deficiency underlying Schatten’s supplementation rationale. A PHOSITA would have had a reasonable expectation of success given Xue’s use of standardized, art-accepted single-cell transcriptomic methodology directly applicable to such comparison.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) in view of Mountain V, et al., (J Cell Biol. 1999 Oct 18;147(2):351-66, in IDS) as applied to claims 30-31 above, and further in view of Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS).
The teachings of Schatten are incorporated herein by reference to the respective 103 rejections above, namely the teaching that HSET restoration corrects multipolar/disorganized spindles into properly organized (bipolar) spindles, [0058].
Schatten does not expressly recite assessment of spindle morphology by fluorescence or polarized light microscopy.
Rawe teaches routine use of immunofluorescence microscopy to assess spindle-associated protein localization and spindle morphology in oocytes.
It would have been obvious to a PHOSITA to apply Rawe’s fluorescence-microscopy assessment technique to confirm the bipolar spindle outcome Schatten’s HSET restoration produces. A PHOSITA would have been motivated to do so as a standard, art-accepted means of visualizing and confirming spindle morphology. A PHOSITA would have had a reasonable expectation of success given the routine, well-established nature of immunofluorescence-based spindle assessment.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Schatten GP, et al., (US20100242125A1, in IDS) in view of Rawe VY, et al. (Fertility & Sterility, Volume 84, Supplement 1, S143, 2005, In IDS).
Schatten teaches introducing KIFC1/HSET protein into a human oocyte or zygote by microinjection ([0067]: “microinjection (cytoplasmic transfer and ICNI; CT+ICNI)”), forming a construct in which HSET is associated with the spindle apparatus (¶[0058]).
Schatten does not expressly teach detecting the resulting complex by fluorescence microscopy.
Rawe teaches routine immunofluorescence-based detection of HSET co-localized with the spindle, see methods and results.
It would have been obvious to a PHOSITA to apply Rawe’s detection technique to visualize/confirm the HSET-spindle complex formed by Schatten’s introduction step. A PHOSITA would have been motivated to do so to confirm successful introduction and proper localization of the introduced protein. A PHOSITA would have had a reasonable expectation of success given both references operate on the same protein target in the same general cell type using an art-standard detection modality.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights