DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 06/04/2026 in response to the Non-Final Rejection mailed on 03/10/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claim 44 is cancelled.
4. Claims 34-35, 37-43, and 45-54 are pending.
5. Applicant’s remarks filed on 06/04/2026 in response to the Non-Final Rejection mailed on 03/10/2026 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Nucleotide and/or Amino Acid Sequence Disclosures
6. The objection to the Drawings/Specification under 37 CFR 1.821 is withdrawn in view of applicants’ amendment to the Drawings and Specification to incorporate appropriate sequence identifiers.
Claim Rejections - 35 USC § 112(b)
7. The rejection of claims 34-35 and 37-54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the relative term “substantially” is withdrawn in view of applicants’ amendment to the claims to recite “wherein said substantially maintained is an expression level of said polypeptide of interest after a period of at least 80 generations being at least 85% of the expression level of said polypeptide of interest after 1 generation”.
8. The rejection of claim 43 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the relative term “reduced” is maintained for the reasons of record and the reasons set for below. The rejection has been modified in view of applicants’ amendment to the claims to recite “said wildtype nucleic acid sequence”.
Regarding claim 43, there is insufficient antecedent basis for the limitation “said wild type nucleic acid sequence”. It is suggested that applicants clarify the meaning of the claims.
RESPONSE TO REMARKS: Beginning on p. 10 of applicants’ remarks, applicants contend that the claim 43 is amended to recite “modified GC content is reduced compared to the GC content of the wildtype nucleic acid sequence”.
This argument is found to be not persuasive in view of the modified rejection set forth above.
Claim Rejections - 35 USC § 112(a)
9. The written description rejection of claim 44 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to cancel claim 44.
10. The scope of enablement rejection of claim 44 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims to cancel claim 44.
11. The written description rejection of claim 34-35, 37-43, and 45-54 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
As amended, claims 34, 38-43, and 45-54 are drawn in relevant part to a method for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in least 10% of a plurality of cells of a transgenic microorganism after a period of at least 80 generations of said cell, wherein said substantially maintained is an expression level of said polypeptide interest after a period of at least 80 generations being at least 85% of the expression level of said polypeptide of interest after 1 generation, the method comprising generating a coding sequence encoding a chimeric polypeptide comprising the polypeptide of interest and an essential gene of a target cell optimized thereto for the generation of a chimeric polypeptide in the target cell, wherein said optimized comprises: a modified GC content, at least one less mutation hotspot, a modified codon usage for optimized expression of said coding sequence in said target cell, at least on less epigenetic hotspot, or any combination thereof, comparted to a wildtype nucleic acid sequence encoding any one of: said polypeptide of interest, said essential gene of said target cell, and both; and wherein said chimeric polypeptide retains an essential function of said essential gene in said target cell.
Claim 35 is drawn in relevant part to the method wherein a selected linker provides optimal folding of both the polypeptide of interest and essential gene of said target cell.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “chimeric polypeptides comprising the polypeptide of interest and an essential gene of a target cell” wherein when expressed in a transgenic microorganism cell substantially maintains expression in at least 10% of transgenic cells as encompassed by the claims (i.e. a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9). The specification discloses an actual reduction to practice of the following representative species of the genus of “linkers that provide optimal folding of both the polypeptide of interest and essential gene of said target cell as encompassed by the claims (i.e. a 2A linker). Other than the above disclosed species there is no other drawings or structural formulas disclosed of the infinite number of transgenic cells and optimized essential genes that expressed in a transgenic cell substantially maintains expression of a polypeptide of interest in at least 10% of transgenic cells after a period of 90 generations. There is no other drawings or structural formulas of the infinite number of linkers that provide optimal folding of both the polypeptide of interest and essential gene.
Given what is known in the art about the likely outcome of substitutions on structure, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function of any essential gene of any target cell that can be optimized by GC content, one less mutation hotspot or modified codon usage that results in a transgenic cell that expresses a polypeptide of interest in at least 10% of said cells after at least 80 generations. Accordingly, one of skill in the art would not accept the disclosure of a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9 as being representative of all methods of genetically optimizing the expression of a polypeptide as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of molecular biology and gene editing, fails to satisfy the written description requirement of 35 U.S.C. 112(a).
RESPONSE TO REMARKS: Beginning on p. 11 of applicants’ remarks, applicants in summary contend that the specification expressly contemplates the application of the disclosed methods and one of ordinary skill in the art would readily be able to identify essential genes for any microorganism using publicly available databases to apply the claimed method. Applicants further contend that the specification discloses structural and functional characteristics of linkers sufficient to convey possession of the genus. Applicants contend that amending the claims to microorganisms brings the claims in alignment with the disclosed species.
This argument is found to be not persuasive in view of the modified rejection set forth above. Furthermore, MPEP 2163.II.A.3.(a).ii states "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the genfus]." See Enzo Biochem, S2S F.Sd at 966, 63 USPQ2d at 1615; Noelle v. Ledermon, 355 F.3d 1343,1350, 69 USPQ2d 1508,1514 (Fed. Cir. 2004) (Fed. Cir. 2004)". In the instant case, the genus of modifications to any microorganism expressing a chimeric polypeptides comprising the polypeptide of interest and an essential gene of a target cell wherein when expressed in a transgenic microorganism cell substantially maintains expression in at least 10% of transgenic cells as encompassed by the claims and not limited to those specific chimeric polypeptides disclosed in the specification. In the Federal Circuit decision, Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021), the courts found that for broad claims to a nucleic acid encoding a chimeric T cell receptor with a functional requirement to bind a target, “the written description must demonstrate that the applicant made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus”. In the instant case, the claims are drawn to nucleic acids encoding a chimeric polypeptide of any sequence and structure, and the specification does not disclose sufficient structural features of the claimed chimeric polypeptide that can result in expression of the polypeptide of interest after a period of at least 80 generations. While a person skilled in the art might be able to embark on their own research program to find suitable essential genes to pair with any polypeptide of interest in any microorganism, the four corners of the written description do not demonstrate possession of such. This analysis is consistent with AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) which required an inventor to show “that one has truly invented the genus, i.e. that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus”. As such, the specification fails to disclose an adequate number of species of the infinite possibilities of genetically optimizing any microorganism that are encompassed by the claims.
12. The scope of enablement rejection of claims 34-35, 37-43, and 45-54 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (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; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A) The breadth of the claims: As amended, claims 34, 38-43, and 45-54 are drawn in relevant part to a method for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in least 10% of a plurality of cells of a transgenic microorganism after a period of at least 80 generations of said cell, wherein said substantially maintained is an expression level of said polypeptide interest after a period of at least 80 generations being at least 85% of the expression level of said polypeptide of interest after 1 generation, the method comprising generating a coding sequence encoding a chimeric polypeptide comprising the polypeptide of interest and an essential gene of a target cell optimized thereto for the generation of a chimeric polypeptide in the target cell, wherein said optimized comprises: a modified GC content, at least one less mutation hotspot, a modified codon usage for optimized expression of said coding sequence in said target cell, at least on less epigenetic hotspot, or any combination thereof, comparted to a wildtype nucleic acid sequence encoding any one of: said polypeptide of interest, said essential gene of said target cell, and both; and wherein said chimeric polypeptide retains an essential function of said essential gene in said target cell.
Claim 35 is drawn in relevant part to the method wherein a selected linker provides optimal folding of both the polypeptide of interest and essential gene of said target cell.
(C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: The scope of the claimed methods for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in at least 10% of a plurality of transgenic cells after a period of at least 80 generations is unlimited. The scope of the linkers that provide optimal folding of both the polypeptide of interest and essential gene of the target cell is unlimited.
Methods for stabilizing genetically engineered functions in E. coli by overlapping a sequence with an essential gene was known in the art as taught by Blazejewski et al. (Science, 2019; cited on PTO-892 mailed on 03/10/2026).
Rogozin et al. (Mutation Research, 2003; cited on PTO-892 mailed on 03/10/2026) teach analysis of the nucleotide sequence context of hotspots can provide information on the molecular mechanisms of mutagenesis. However, the determinants of mutation frequency and specificity are complex [see Abstract].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of chimeric polypeptides comprising the polypeptide of interest and an essential gene of a target cell wherein when expressed in a transgenic cell substantially maintains expression in at least 10% of transgenic cells, i.e. a Saccharomyces cerevisiae expressing a coding sequence having the host essential genes Fol3, Nus1, Dfr1, Sec2, Ram2, Tsc13, Ceg1, Sqt1, Kap95 and Cdc9. The specification disclose the following working examples of linkers that provide optimal folding of both the polypeptide of interest and essential gene of said target cell, i.e. a 2A linker. Other than these working examples, the specification fails to disclose any other working examples of transgenic cells, essential genes, and linkers.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
RESPONSE TO REMARKS: Beginning on p. 13 of applicants’ remarks, applicants in summary contend that the specification provides working examples in S. cerevisiae of 10 diverse essential genes, demonstrating that the method works across a representative range of essential gene types within a microorganism and contend that the level of predictability for essential gene function in microorganisms is higher than in complex multicellular organisms. Applicants further contend that the specification provides sufficient guidance on linker selection criteria.
This argument is found to be not persuasive in view of the modified rejection set forth above. The genus of methods for genetically optimizing the expression of a polypeptide of interest such that it is substantially maintained in at least 10% of a plurality of transgenic microorganism cells after a period of at least 80 generations is no limited to those disclosed in the specification. In the Federal Circuit decision of Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1156 (Fed. Cir. 2019), the court stated that “the key enablement question is whether a person of ordinary skill in the art would know, without undue experimentation, which [species] would be effective….because of the many thousands of [species] which need to be screened for…efficacy, the quantity of experimentation needed is large and weighs in favor of non-enablement.” In the instant case, the number is not thousands but an infinite number of essential gens across any microorganism that result in expression of a polypeptide of interest being maintained in at least 10% of a plurality of transgenic microorganism cells after a period of at least 80 generations, and as such, the quantity of experimentation would be many orders of magnitude more than that in Idenix. It would not routine in the art to screen by a trial an error process of all essential genes across all microorganisms as broadly encompassed by the claims. Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Conclusion
13. Status of the claims:
Claims 34-35, 37-43, and 45-54 are pending.
Claims 34-35, 37-43, and 45-54 are rejected.
No claims are in condition for an allowance.
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 PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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