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 .
DETAILED ACTION
This application is a divisional of 16/966,768, issued as US Patent No. 12,077,786, which is a 371 of PCT/US2019/016403.
The response filed on July 6, 2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 180-185) with an election of species of (1) CHO for the cell, (2) CHO P5CS as the P5CS, (3) SREBF1 as the LLM, and (4) PGK as the control sequence in the reply filed on July 6, 2026 is acknowledged.
Claims 170-179 and 181 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (claims 170-179) and species (claim 181), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 6, 2026.
Status of Claims
Claims 170-185 are pending.
Claims 170-179 and 181 are withdrawn.
Claims 180 and 182-185 are under examination.
Claim for Domestic Priority
Applicants' claim for domestic priority under 35 USC 119(e) to US provisional application 62/625,773, filed 02/02/2018, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 14, 2026, October 20, 2025, and July 22, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, page 13, for example. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01. Applicant’s cooperation is requested in reviewing the specification for additional embedded hyperlink and/or other form of browser-executable code that may be present in the specification and making the appropriate correction(s).
Claim Objections
Claims 180, 182, and 184 are objected to due to the recitations of “GS-KO”, “P5CS”, “LMM”, “SREBF-1”, and “GS”. Abbreviation/acronym unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation/acronym is used. 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.
Claim 180 and claims 182-185 depending therefrom 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 180 recites the phrase “comprising a heterologous nucleic acid sequence i) a nucleic acid sequence that when expressed.. and ii) a nucleic acid sequence capable e of..”. The metes and bounds of the phrase in the context of the claim are not clear. It is unclear (A) if the cell comprising the “heterologous nucleic acid” recited in line 1 comprises the nucleic acids sequence of i) and ii) or (B) if the cell comprises (1) “heterologous nucleic acid” recited in line 1 and the nucleic acids sequence of i) and ii) comprises the nucleic acids sequence of i) and ii). Clarification is requested.
For examination purposes, the claim has been interpreted as a cell comprising a heterologous nucleic acid comprising the nucleic acids sequence of i) and ii).
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claims 180 and 182-185 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' In the instant case, the claims have been broadly interpreted to encompass (A) any GS-KO cell or CHO GS-KO comprising (B) a heterologous nucleic acid when expressed results in an elevated level of P5CS and (C) a heterologous nucleic acid expressing any lipid metabolism modifier or any isoform or functional fragment of SREBF-1. Therefore, the claims are directed to (A) CHO GS-KO cell or a genus of GS-KO cells comprising (B) a heterologous nucleic acid expressing P5CS and (C) a heterologous nucleic acid expressing a genus of lipid metabolism modifiers or genus of isoforms or functional fragments of SREBF-1.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The GS gene must be known in order to inactivate said gene in any cell. The recitation of “GS-KO cell” fails to provide a sufficient description of the genus of the cells as it does not provide any definition of the structural or functional features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any functional or structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
CHO GS-KO cells expressing heterologous polynucleotides were known in the art, see Fan (Improving the efficiency of CHO cell line generation using glutamine synthetase gene knockout cells. Biotechnol Bioeng. 2012 Apr;109(4):1007-15. Epub 2011 Nov 21 – form PTO-892) and Budge (WO 2017/191165 – form PTO-892). SREBF-1, a LMM, was also known in the art, see Budge (WO 2017/191165 – form PTO-892). However, neither the prior art nor the instant specification provide guidance on knocking out a GS gene in any cells and expressing any lipid metabolism modifiers or any isoforms or functional fragments of SREBF-1
The specification is limited to a CHO GS-KO expressing a heterologous polynucleotide encoding P5CS and a heterologous polynucleotide encoding SREBF-1. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the one example described above is not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
Futher, the specification does not provide an actual reduction to practice of the genus because the specification fails to disclose the structure of the GS gene from non-CHO cells which must be known in order to inactivate said gene in any cell. The specification does not disclose the isolation or cloning of any non-CHO GS gene. Because a CHO cell comprising a knock of its GS gene is not representative of the entire genus any cell and the specification does not disclose structural features shared by members of the genus, the description of the above CHO GS-KO would not have put the application in possession of the common structural attributes or features shared by members of the genus that structurally distinguish the members of the genus from other materials at the time of filing.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 180 and 182-185.
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 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 180 and 182-185 is/are rejected under 35 U.S.C. 103 as being unpatentable over Famili (US 2016/0160236 – form PTO-1449), Fan (Improving the efficiency of CHO cell line generation using glutamine synthetase gene knockout cells. Biotechnol Bioeng. 2012 Apr;109(4):1007-15. Epub 2011 Nov 21 – form PTO-892), and Budge (WO 2017/191165 – form PTO-892).
Regarding claims 180 and 185, Famili discloses selectable marker systems for CHO cells, such as dihydrofolate reductase (DHFR) or glutamine synthetase (GS), for producing a product of interest, which are well established in the art ([0007]). Famili discloses new selectable marker system for CHO cells for producing a product of interest ([0023]). Famili disclose using pyrroline-5-carboxylate synthetase (P5CS and synonymous with pyrroline-5-carboxylate synthase), involved in proline synthesis, as a selectable marker (Table 1 Target “5. P5CS” at page 26, [0181]-[0185], and Example III). Famili discloses providing a CHO cell comprising a vector/heterologous nucleic acid sequence comprising (i) a heterologous nucleic acid encoding P5CS and (ii) a heterologous nucleic acid sequence encoding a protein of interest and (b) culturing the cell in the presence of media lacking proline, which is required for growth of the cell, under conditions sufficient to allow for growth the cell due to expression of the nucleic acid encoding P5CS (Figure 7, [0016], [0023], [0030]-[0034], and [0185]-[0187]).
Regarding claim 183, Famili discloses that the heterologous nucleic acid sequence is integrated into the host genome ([0036]).
Famili does not disclose a dual selection system using GS and P5CS as selectable markers, wherein the CHO cell is a CHO GS knock-out cell comprising i) heterologous nucleic acid sequence when expressed results in elevated levels of P5CS and ii) heterologous nucleic acid expressing a lipid metabolism modifier (LMM) or SREBF-1. However, Famili discloses using additional selectable markers in combination with the P5CS selectable marker described above for a dual selection system ([0039]).
Regarding claims 180, 184, and 185, Fan discloses a CHOK1SV GS knockout (GS-KO) cell line having improved selection efficiency (abstract, page 1008, 1st paragraph and 4th paragraph “Experimental Design”). Fan discloses that since selection of recombinant cell lines in the GS-CHO system is based on the balance between the expression of the GS gene introduced by the expression plasmid and the addition of the GS inhibitor, L-MSX, the expression of GS from the endogenous GS gene in parental CHO cells will likely interfere with the selection process. To study endogenous GS expression’s potential impact on selection efficiency, GS-knockout CHOK1SV cell lines were generated using the zinc finger nuclease (ZFN) technology designed to specifically target the endogenous CHO GS gene. GS enzyme function disruption was confirmed by the observation of glutamine-dependent growth of all GS-knockout cell lines (abstract). Fan discloses that the resulting GS-knockout cell lines were fully characterized, confirming gene disruption, and subsequently evaluated for selection stringency improvement in an industrial cell culture process (page 1008, right column).
Regarding claims 180 and 182, Budge discloses a CHOK1SV GS-KO cell expressing SREBF-1, a lipid metabolism modulator (LLM) (page 8, lines 7-8, page 10, line 23 through page 11, line 5, page 17, lines 26-33, line 62, lines 14-20, lines 29-35, and Example 1). Budge discloses modulating lipid metabolism to achieve improved production and quality of recombinant products (abstract). Budge discloses that modulation of the lipid metabolism, e.g., by modulating one or more lipid metabolism pathways, can be used to engineer cells that produce higher yields of products and products with improved quality (page 2, lines 5-7).
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was effectively filed to modify the CHO cell of Famili by (1) knocking out the GS gene thereby allowing for a dual selection marker system using a combination of P5CS and GS as selectable markers, and (2) expressing SREBF-1. One having ordinary skill in the art would have been motivated to do so in order to (1) improve selection efficiency and (2) produce higher yields of products and products with improved quality. One of ordinary skill in the art would have had a reasonable expectation of success since Famili teaches using P5CS and GS as the selectable marker in CHO cell, Fan discloses using a GS-KO CHO, and Budge teaches a CHO GS-KO cell expressing SREBF-1.
Therefore, the above references render claims 180 and 182-185 prima facie obvious.
Conclusion
Claims 170-185 are pending.
Claims 170-179 and 181 are withdrawn.
Claims 180 and 182-185 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YONG D PAK/Primary Examiner, Art Unit 1652
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