DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Applicant should note that the examiner assigned to this case has changed.
Election/Restrictions
Applicant's election with traverse of Invention II, presently claims 10-17, in the reply filed on 2/23/2026 is acknowledged. The traversal is on the ground(s) that there would be no serious search burden. This is not found persuasive because as burden consists not only of specific searching of classification codes, but also of searching multiple databases for foreign references and literature searches, and burden also resides in the examination of independent claim sets for eligibility, clarity, enablement, description, and double patenting issues. Finally, because the broadest reasonable interpretation of composition of matter or apparatus/system claims would typically apply differing patentable weight to statements of intended use then method claims (see M.P.E.P. § 2111.02(II) and 2111.04(I)), there remains a serious burden as a search of the composition of matter and/or apparatus/system claims may not necessarily and simultaneously capture all of the limitations of the method claims.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-9 and 18-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 2/23/2026.
Claims 10-17 are under consideration on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
No information disclosure statement has been filed in the instant application. Applicant is reminded of the duty to disclose information material to patentability as set forth in 37 C.F.R 1.56 and M.P.E.P. § 2001-2002.
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 10-17 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 limitation together with a narrow 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, claim 10 recites the broad recitation of “cellular and/or nuclear deformation”, and the claim also recites “cell and nuclear deformation”, “deforming a mammalian cell and its nucleus”, and “nuclear deformation causes changes in DNA/chromatin modification and organization” which are all the narrower statement of the 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. Correction is required.
Regarding claim 10, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Correction is required.
In so much that claims 11-17 depend from claim 10 and do not resolve the point of confusion, these claims must be rejected with claim 10 as indefinite.
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.
Claims 10-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sharei et al. (US 2014/0287509; Reference A) as evidenced by Bionumbers (webpage, “How big is a human cell?” (2021), 4 pages; Reference U) and Lammerding (Compr Physiol. (2011), 1(2), 46 page author manuscript; Reference V).
In view of the indefiniteness rejections above and in the interest of compact prosecution, this rejection addresses the embodiment of cellular deformation for claim 10.
Sharei teaches a method of mechanically deforming a mammalian cell and its nucleus comprising: 1) selecting human fibroblasts or hepatocytes for mechanical deformation in a microfluidic cell culture system, wherein the size of fibroblasts and mammalian cell nucleus is known and so determined as evidenced by Bionumbers (Table 1) and Lammerding (the paragraph spanning pages 2-3), respectively, wherein the system comprises: 1a) an inlet reservoir configured to receive cells; 1b) an outlet reservoir to collect cells from the microfluidic system; and 1c) at least one channel coupling the inlet reservoir to the outlet reservoir; and 2) disposing the mammalian cell in the microfluidic cell culture system such that the mammalian cell contacts sides of the at least one channel so as to undergo cellular deformation as the cell moves from the inlet reservoir through the at least one channel to the outlet reservoir, such that the cell deformation cause changes in DNA/chromatin modification and organization as measured by bisulfite sequence, and 3) differentiating said fibroblasts into induced pluripotent stem cells (iPSCs) by introducing 4 reprogramming factor proteins (i.e. c-Myc, Klf4, Oct4, and Sox3) to the mechanically deformed cells (Example 6, particularly at [0224]-0226] and [0235] and Fig. 36-38), anticipating claims 10-12. Sharei teaches further differentiating iPSCs into dopamine neurons (Example 6 at [0242]), anticipating claim 13.
In a separate embodiment, Sharei teaches a method of mechanically deforming a mammalian cell and its nucleus comprising: 1) selecting Dc2.4 dendritic cells, human fibroblasts, HeLa cells, and mouse embryonic stem cells for mechanical deformation in a microfluidic cell culture system, wherein the size of mammalian cells and their nuclei is known and so determined as evidenced by Bionumbers (Table 1) and Lammerding (the paragraph spanning pages 2-3), respectively, wherein the system comprises: 1a) an inlet reservoir configured to receive cells; 1b) an outlet reservoir to collect cells from the microfluidic system; and 1c) at least one channel coupling the inlet reservoir to the outlet reservoir; and 2) disposing the mammalian cell in the microfluidic cell culture system such that the mammalian cell contacts sides of the at least one channel so as to undergo cellular deformation as the cell moves from the inlet reservoir through the at least one channel to the outlet reservoir, such that the cell deformation cause changes in DNA/chromatin modification and organization as measured by introducing siRNA (e.g. to knockdown GFP expression in GFP-expressing HeLa cells (Example 2, particularly at [0162]-[0163] and Fig. 28-29; also particularly [0171]-[0176] for device features and cell culturing), anticipating claims 10, 11, and 14.
Claims 10 and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ding et al. (Nat Biomed Eng. (2017), 1, 15 page author manuscript; Reference W) as evidenced by Bionumbers (webpage, “How big is a human cell?” (2021), 4 pages; Reference U) and Lammerding (Compr Physiol. (2011), 1(2), 46 page author manuscript; Reference V).
In view of the indefiniteness rejections above and in the interest of compact prosecution, this rejection addresses the embodiment of cellular and nuclear deformation for claim 10.
Ding teaches a method of mechanically deforming a mammalian cell and its nucleus comprising: 1) selecting HeLa cells for mechanical deformation in a microfluidic cell culture system, wherein the size of mammalian cells and their nuclei is known and so determined as evidenced by Bionumbers (Table 1) and Lammerding (the paragraph spanning pages 2-3), respectively, wherein the system comprises: 1a) an inlet reservoir configured to receive cells; 1b) an outlet reservoir to collect cells from the microfluidic system; and 1c) at least one channel coupling the inlet reservoir to the outlet reservoir (Fig. 1); and 2) disposing the mammalian cell in the microfluidic cell culture system such that the mammalian cell contacts sides of the at least one channel so as to undergo cellular deformation as the cell moves from the inlet reservoir through the at least one channel to the outlet reservoir, such that the cell and nuclear deformation cause changes in DNA/chromatin modification and organization as measured by delivery of plasmid DNA encoding for GFP into the nucleus of the cells (DFE in Fig. 3c; the first paragraph on page 5; the paragraph spanning pages 2-3 for nuclear envelope rupture), anticipating claims 10, 14, and 15. Ding teaches that the disruption and field enhanced (DFE) methods apply an electric field for 50-500 μs (i.e. 0.05-0.5 ms) with a throughput of 100,000-500,000 cells/s per chip per run wherein each run took 5-20 seconds (the 2nd full paragraph on page 3), anticipating the time ranges of claim 16 with sufficient specificity as Ding teaches a narrower time range than claimed (see M.P.E.P. § 2131.03).
Claims 10 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suang et al. (Small (2016), 12(42), 5873-5881; Reference X) as evidenced by Lammerding (2015; Reference U).
In view of the indefiniteness rejections above and in the interest of compact prosecution, this rejection addresses the embodiment of cellular deformation for claim 10.
Suang teaches a method of mechanically deforming a mammalian cell and its nucleus comprising: 1) selecting T cells, and pancreatic cell lines BxPc3 and GFP-expressing PANC-1 for mechanical deformation in a microfluidic cell culture system and determining the diameter of the cells (Fig. 2a) and wherein the size of mammalian cell nuclei is known and so determined as evidenced by Lammerding (the paragraph spanning pages 2-3), wherein the system comprises: 1a) an inlet reservoir configured to receive cells; 1b) an outlet reservoir to collect cells from the microfluidic system; and 1c) at least one channel coupling the inlet reservoir to the outlet reservoir (schematic of Figure 1); and 2) disposing the mammalian cell in the microfluidic cell culture system such that the mammalian cell contacts sides of the at least one channel so as to undergo cellular deformation as the cell moves from the inlet reservoir through the at least one channel to the outlet reservoir, such that the cell deformation loads the cells with fluorophore-conjugated macromolecule as confirmed by FACS (Figure 2E-F, and the full paragraph on pages 5875), anticipating claim 10. Suang teaches loading GFP-expressing PANC-1 cells with fluorophore-conjugated macromolecule by deforming the cells through 7 μm wide constriction, adding said loaded PANC-1 cells to healthy patient whole blood, and verifying PANC-1 cell identity by genomic sequencing and detection of a targeted loss of heterozygosity in TP53, a missense mutation at codon 273, and a heterozygous mutation in KRAS codon 12 (Fig. 3A and subheading 2.2 on pages 5876-5877), anticipating claim 17.
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.
Claims 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sharei et al. (US 2014/0287509; Reference A) as evidenced by Bionumbers (webpage, “How big is a human cell?” (2021), 4 pages; Reference U) and Lammerding (Compr Physiol. (2011), 1(2), 46 page author manuscript; Reference V).
The teachings of Sharei as evidenced by Bionumbers and Lammerding are relied upon as set forth above in rejecting claims 10-14 as anticipated under 35 U.S.C. § 102.
Regarding claim 15, Sharei further teaches delivering DNA, RNA, siRNA, or protein to primary fibroblasts and stem cells for cell reprogramming (e.g. DNA or mRNA of gene(s) to be expressed) (Claim 54).
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further add exogenous nucleic acids comprising DNA and/or mRNA of gene(s) to be expressed (e.g. c-Myc, Klf2, Oct4, and Sox2) to the primary fibroblasts or stem cells of Sharei such that the cells are reprogrammed to iPSCs in Sharei’s mechanical deformation and transformation methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so and the skilled artisan would have been motivated to do so because Sharei expressly considers DNA and mRNA as alternative embodiments and useful for THE SAME PURPOSE to generate iPSCs. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 16 is alternatively rejected under 35 U.S.C. 103 as being unpatentable over Ding et al. (Nat Biomed Eng. (2017), 1, 15 page author manuscript; Reference W) as evidenced by Bionumbers (webpage, “How big is a human cell?” (2021), 4 pages; Reference U) and Lammerding (Compr Physiol. (2011), 1(2), 46 page author manuscript; Reference V).
The teachings of Ding as evidenced by Bionumbers and Lammerding are relied upon as set forth above in rejecting claims 10, 14, and 15 as anticipated under 35 U.S.C. § 102.
Regarding claim 16, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). In this case, Ding teaches an overlapping time range with the claimed range in methods of method of mechanically deforming a mammalian cell and its nucleus and so the claimed range must be held prima facie obvious absent any showing of criticality to the contrary (see M.P.E.P. § 2144.05).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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