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 11/18/2025 in response to the Non-Final Rejection mailed on 08/22/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 32, 36, and 43-45 are cancelled.
4. Claims 1-31, 33-35, 37-42, and 46-50 are pending.
5. Applicant’s remarks filed on 11/18/2025 in response to the Non-Final Rejection mailed on 08/22/2025 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.
Information Disclosure Statement
6. The IDS filed on 02/06/2026 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Claim Rejections - 35 USC § 112(b)
7. The rejection of claims 1-31 and 41-42 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 forth below.
Regarding claims 1-31 and 41-42, the term "reduced" is a relative term which renders the claim indefinite. The term “reduced" is a term of degree and it is unclear what the term is being compared relative to. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165.
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that the “reduced” is an adjective that describes that state of the physiology of the recombinant cell and not a relative process.
This argument is found to be not persuasive because while the examiner acknowledges that the term relates to a state of physiology of the recombinant cell, there is no indication in the claim of what that cell is being compared to. In other words, the what is the “reduced” activity being compared relative to.
8. The rejection of claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the recitation of “wherein the recombinant cell is obtained from ATCC Deposit No. PTA-126975” is maintained for the reasons of record and the reasons set forth below.
Regarding claim 6, the recitation of “wherein the recombinant cell is obtained from ATCC Deposit No. PTA-126975” is indefinite because it is unclear what the metes and bounds of this phrase is intended to encompass. It is unclear if the recombinant cell is the recited deposited strain or a modified strain from the deposited strain. It is suggested that applicants clarify the meaning of the claims.
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that the claim has been amended to recite that the recombinant cell is obtained from ATCC Deposit No. PTA-126975.
This argument is found to be not persuasive because it is still unclear whether the recombinant cell is a modified version of ATCC Deposit No. PTA-126975 or is ATCC Deposit No. PTA-126975.
9. Claims 37-42 are newly 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. This new grounds of rejection is necessitated by applicants’ amendment to the claims to cancel claim 36.
Regarding claims 37 (claims 38-42 dependent therefrom), the recitation of “The method of claim 36” is indefinite because claim 36 has been cancelled. Accordingly, it is unclear which claim claim 37 is intended to be dependent upon. It is suggested that applicants clarify the meaning of the claims. In the interest of compact prosecution, claim 37 will be interpreted as being dependent upon claim 33.
Claim Rejections - 35 USC § 112(a)
10. The written description rejection of claim 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the amendment to the claims to cancel claim 36.
11. The scope of enablement rejection of claim 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the amendment to the claims to cancel claim 36.
12. The written description rejection of claims 1-31 and 33-42 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’ amendments 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 1-16 are drawn in relevant part to a method of producing a protein containing one or more sulfide linkages comprising expressing the protein from a recombinant cell containing a genome and an expression vector that encodes the protein sequence, wherein the recombinant cell has a reduced activity of a disulfide reductase enzyme. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claims 17-30 are drawn in relevant part to a method of producing a peptide comprising expressing the peptide in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claim 31 is drawn in relevant part to a method of producing a peptide containing disulfide bonds comprising expressing the peptide in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claims 33-42 are drawn in relevant part to a method of producing a protein comprising expressing a preprotein in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus “recombinant cell wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes” as encompassed by the claims (i.e. an E. coli cell in which the gor gene has been deleted). Other than the above disclosed species, there are no other drawings or other structural formulas of recombinant cells wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes as encompassed by the claims. While an E. coli comprising a gor gene deletion was known in the prior art as evidenced by Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025), there is no other prior art or disclosed teaching regarding which modifications to any recombinant cell results in reduced disulfide reductase enzyme activity. The breadth of the claims encompass and modification to the recombinant cell by mutation, substitution, or inhibitor of the gene encoding disulfide reductase enzymes or genes encoding proteins and transcription factors involved in the expression of said enzymes. 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. Accordingly, one of skill in the art would not accept the disclosure of E. coli comprising a gor gene deletion disclosed above as being representative of all modifications to any recombinant cell that results in reduced activity of disulfide reductase enzymes as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of genetic modification, fails to satisfy the written description requirement of 35 U.S.C. 112(a), or first paragraph.
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that the claim has been amended to recite “a reduced activity of a disulfide reductase enzyme” and as such the rejection should be withdrawn.
This argument is found to be not persuasive because for the reasons already of record and the reasons set forth below. As stated previously, MPEP 2163.11.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 and as stated in the modified rejection above, the structure of the modifications to a recombinant cell that results in reduced disulfide reductase enzyme activity is unlimited and includes any modification to the recombinant cell that results in the desired reduction. As such, the genus as encompassed by the claims is highly variant, and the specification fails to disclose an adequate number of species to describe the entire genus of recombinant cells having reduced activity of a disulfide reductase as encompassed by the claims.
13. The scope of enablement rejection of claims 1-31 and 33-42 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’ amendments 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 1-16 are drawn in relevant part to a method of producing a protein containing one or more sulfide linkages comprising expressing the protein from a recombinant cell containing a genome and an expression vector that encodes the protein sequence, wherein the recombinant cell has a reduced activity of a disulfide reductase enzyme. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claims 17-30 are drawn in relevant part to a method of producing a peptide comprising expressing the peptide in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claim 31 is drawn in relevant part to a method of producing a peptide containing disulfide bonds comprising expressing the peptide in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Claims 33-42 are drawn in relevant part to a method of producing a protein comprising expressing a preprotein in a recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes. The modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
(C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the scope of the claimed modifications to any recombinant cell that results in reduction in activity of a disulfide reductase enzyme is unlimited.
Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) discloses an E. coli strain comprising reduced activity of one or more disulfide reductase enzymes comprising a deletion of a gor gene.
The breadth of the claims encompass and modification to the recombinant cell by mutation, substitution, or inhibitor of the gene encoding disulfide reductase enzymes or genes encoding proteins and transcription factors involved in the expression of said enzymes. To this end, it is well-known in the prior art that the amino acid sequence of a polypeptide determines the polypeptide’s functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g., multiple substitutions.
It is well-known in the art that even a single amino acid alteration can alter the folding of a polypeptide. See, e.g., MPEP 2144.08.II.A.4.(c), which states, “[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (“the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990).”
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working example of recombinant cell wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes, i.e. an E. coli cell in which the gor gene has been deleted. Other than this working example, the specification fails to disclose any other working examples of modifications to any recombinant cell that results in reduced activity of one or more disulfide reductase enzymes. Moreover, the specification fails to provide guidance regarding modification(s) to said recombinant cells that maintain the desired activity.
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. 9 of applicants’ remarks, applicants contend that the claim has been amended to recite “a reduced activity of a disulfide reductase enzyme” and as such the rejection should be withdrawn.
This argument is found to be not persuasive because the structure of the modifications to a recombinant cell that results in reduced disulfide reductase enzyme activity is unlimited and includes any modification to the recombinant cell that results in the desired reduction. As such, it was not routine for one of skill in the art to make and test each possible modification to result in reduced disulfide reductase enzyme activity. Such experimentation is highly unpredictable and unnecessarily undue.
14. The enablement rejection of claim 6 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 is maintained for the reasons of record and the reasons set forth below. The claim(s) 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.
The specification fails to provide an enabling disclosure, because the specification does not provide evidence that the claimed biological materials are: (1) known and readily available to the public; (2) reproducible from the written description; or, (3) deposited in compliance with the criteria set forth in 37 CFR 1.801-1.809.
The specification lacks complete deposit information for the strain PTA-126975. Because it is not clear that the recombinant cell designated PTA-126975 is known and publicly available or can be reproducibly isolated without undue experimentation, and because the invention of claim 6 claims or uses the recombinant cell, a suitable deposit for patent purposes is required. Accordingly, filing of evidence of the reproducible production of the mutant bacterial strain is necessary to practice the instant invention or filing of evidence of deposit is required. Without a publicly available deposit of the above mutant bacterial strain, one of ordinary skill in the art could not be assured of the ability to practice the invention as claimed. Exact replication of the mutant bacterial strain is an unpredictable event. Applicants must comply with the criteria set forth in 37 CFR 1.801-1.809.
If the deposits are made under the terms of the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific strain PTA-126975, have been deposited under the Budapest Treaty, that the strain PTA-126975, will be irrevocably and without restriction or condition released to the public upon the issuance of a patent and that the strain PTA-126975, will be replaced should they ever become non-viable, would satisfy the deposit requirement made herein.
If the deposits have not been made under the Budapest Treaty, then in order to certify that the deposits meet the criteria set forth in 37 CFR 1.801-1.809, applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number.
For each deposit made pursuant to these regulations, the specification shall contain:
The accession number for the deposit;
The date of the deposit;
A description of the deposited biological material sufficient to specifically identify it and to permit examination; and
The name and address of the depository.
A viability statement for each deposit of a biological material not made under the Budapest Treaty on the International Recognition of the deposit of Microorganisms for the Purposes of Patent Procedure must be filed in the application and must contain:
The name and address of the depository;
The name and address of the depositor;
The date of deposit;
The identity of the deposit and the accession number given by the depository;
The date of the viability test;
The procedures used to obtain a sample if the test is not done by the depository; and
A statement that the deposit is capable of reproduction.
Applicant must assure that:
Access to the deposit will be available during pendency of the patent application making reference to the deposit.
All restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent.
In the instant case, the specification fails to disclose that the strain PTA-126975 has been deposited under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations, provides no address of the depository, the date of the viability test, procedures used to obtain a sample if the test is not done by the depository, a statement that the deposit is capable of reproduction, and there is not an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the strain PTA-126975, have been deposited under the Budapest Treaty, that the strain PTA-126975, will be irrevocably and without restriction or condition released to the public upon the issuance of a patent and that the strain PTA-126975, will be replaced should they ever become non-viable. A verified statement is required from a person in a position to corroborate that the biological material described in the specification as filed is the same as that deposited in the depository, stating that the deposited material is identical to the biological material described in the specification and was in the Applicant’s possession at the time the application was filed.
As a possible means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit along with the necessary statements in order to meet the criteria set forth in 37 CFR 1.801-1.809.
Applicant’s attention is directed to In re Lundak, 773 F.2nd. 1216, 227 USPQ 90 (CAFC 1985) and 37 CRF 1.801-1.809 for further information concerning deposit practice.
RESPONSE TO REMARKS: Beginning on p. 9 of applicants’ remarks, applicants contend that the ATCC confirmation of viability statement is attached and that the deposit was made in accordance with the Budapest Treaty.
This argument is found to be not persuasive because there is no affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the strain PTA-126975, have been deposited under the Budapest Treaty, that the strain PTA-126975, will be irrevocably and without restriction or condition released to the public upon the issuance of a patent and that the strain PTA-126975, will be replaced should they ever become non-viable
Claim Rejections - 35 USC § 102
15. The rejection of claims 33-35 under 35 U.S.C. 102(a)(1) as being anticipated by Peters et al. (US Patent Application Publication 2013/0281671 A1; cited on PTO-892 mailed on 08/22/2025) is withdrawn in view of applicants’ amendment to the claims to recite “wherein the protease gene is integrated into the genome of the recombinant cell and encodes a methionine aminopeptidase”.
16. The rejection of claims 46-50 under 35 U.S.C. 102(a)(1) as being anticipated by Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) is withdrawn in view of applicants’ amendment to claim 46 to recite “the recombinant cell contains a gor mutation”.
Claim Rejections - 35 USC § 103
17. The rejection of claims 36-40 under 35 U.S.C. 103 as being unpatentable over Peters et al. (US Patent Application Publication 2013/0281671 A1; cited on PTO-892 mailed on 08/22/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) is withdrawn for the reasons set forth above regarding Peters et al.
18. The rejection of claims 41-42 under 35 U.S.C. 103 as being unpatentable over Peters et al. (US Patent Application Publication 2013/0281671 A1; cited on PTO-892 mailed on 08/22/2025) in view of Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) is withdrawn for the reasons set forth above regarding Peters et al.
19. The rejection of claims 1-29 and 31 under 35 U.S.C. 103 as being unpatentable over Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to incorporate claims 46-50, which is necessitated by applicants’ amendment to claim 46 to recite “contains a gor mutation”.
Claims 1-29, 31 and 46-50 are rejected under 35 U.S.C. 103 as being unpatentable over Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023).
20. As amended, claims 1-16 are drawn to a method of producing a protein containing one or more sulfide linkages comprising: expressing the protein from a recombinant cell containing a genome and an expression vector that encodes the protein sequence, wherein the recombinant cell has a reduced activity of a disulfide reductase enzyme, and the N-terminus of the protein contains a methionine; expressing a peptidase from a gene of the recombinant cell, wherein the peptidase removes the methionine from the N-terminus of the protein expressed; and isolating the protein.
Claims 17-29 are drawn to a method of producing a peptide comprising: expressing the peptide in a recombinant cell containing a gene that encodes a peptidase enzyme, wherein the gene that encodes the peptidase enzyme is integrated into the genome of the recombinant cell, wherein the recombinant cell has reduced activity of one or more disulfide reductase enzymes, wherein the reduced activity of one or more disulfide reductase enzymes results in a shift in the redox state of the cytoplasm to a more oxidative state as compared to a recombinant cell that does not have reduced activity of one or more disulfide reductase enzymes, and wherein the peptide contains an N-terminal methionine; expressing the peptidase enzyme which removes the N-terminal methionine from the peptide; and isolating the peptide.
Claim 31 is drawn to a method of producing a peptide containing disulfide bonds, comprising: expressing the peptide in a recombinant cell containing a gene that encodes a peptidase enzyme, wherein the peptide is encoded in an expression vector, wherein the gene that encodes the peptidase enzyme is integrated into the genome of the recombinant cell, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes, wherein the recombinant cell is E. coli, and wherein the peptide contains a N-terminal methionine; expressing the peptidase enzyme which removes the N-terminal methionine fro the peptide; and isolating the peptide from within the cytoplasm of the recombinant cell, wherein the peptide isolated is soluble.
As amended, claims 46-50 are drawn to a method of producing a peptide comprising: expressing the peptide in a recombinant cell wherein the expressed peptide contain an N-terminal methionine, and the recombinant cell contains a gor mutation and a gene that encodes a peptidase; expressing the peptidase gene such that the N-terminal methionine is cleaved from the expressed peptide; and isolating the peptide.
21. With respect to claim 1, Oganesyan et al. teach a method for producing a soluble CRM197 protein from E. coli comprising expressing the protein from an E. coli (interpreted as containing a genome) containing an expression vector that encodes the protein sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, and purifying the expressed protein [see Abstract; p. 3].
With respect to claim 2, Oganesyan et al. teach the method wherein the protein expressed is CRM197, which is a diphtheria toxin [see p. 2, lines 3-10].
With respect to claim 3, Oganesyan et al. teach the method wherein the recombinant cell has a reduced activity of only one disulfide reductase enzyme [see p. 3].
With respect to claim 4, Oganesyan et al. teach the method wherein the recombinant cell has a reduced activity of more than one disulfide reductase enzyme [see p. 3].
With respect to claim 5, Oganesyan et al. teach the method wherein the recombinant cell is an E. coli cell[see p. 4, lines 11-12].
With respect to claim 6, Oganesyan et al. teach the method wherein the recombinant E. coli comprises a deletion of gor gene [see p. 4, lines 11-12; p. 9]. Although Oganesyan et al. does not explicitly teach wherein the cell is obtained or derived from ATCC Deposit No. PTA-126975, given the indefiniteness of this claim, it is the examiner’s position that the Oganesyan et al. strain can be interpreted as derived from said strain.
With respect to claim 8, Oganesyan et al. teach the method wherein the expression vector contains a ribosome binding site, an initiation codon, and/or an expression enhancer region [see p. 4, lines 8-9].
With respect to claim 9, Oganesyan et al. teach the method wherein the expression vector contains an inducible first promoter and expressing the protein comprises inducing the inducible promoter with a first inducing agent [see p. 4, lines 3-24].
With respect to claim 10, Oganesyan et al. teach the method wherein the expression vector comprises one or more inducible promoters [see p. 4, lines 3-24; p. 7, bottom; p. 12].
With respect to claim 11, Oganesyan et al. teach the method wherein the expression vector contains expressible sequences, an inducible first promoter and expressing the protein comprises inducing the inducible first promoter with a first inducing agent, the gene contains an inducible second promoter and inducing with a second inducing agent, wherein the first and second inducing agents are the same [see 4, lines 3-24; p. 7, bottom; p. 11, bottom bridging to p. 12].
With respect to claim 13, Oganesyan et al. teach the method wherein the isolating comprises chromatography [see p. 4, lines 25-27].
With respect to claim 14, Oganesyan et al. teach the method wherein the chromatography comprises a dextran sulfate resin, an active sulfate resin, a phosphate resin, a heparin resin, or a heparin-like resin [see p. 4, lines 25-27].
With respect to claim 15, Oganesyan et al. teach the method further comprising conjugating the isolated protein with a chemical compound [see p. 4, bottom; p. 14, lines 22-24].
With respect to claim 16, Oganesyan et al. teach the method wherein the chemical compound comprises a polysaccharide, protein, peptides, oligosaccharides and haptens [see p. 14, lines 22-24].
With respect to claim 17, Oganesyan et al. teach a method of producing a CRM peptide from E. coli comprising expressing the protein from an E. coli (interpreted as containing a genome) containing an expression vector that encodes the peptide sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, wherein the reducing activity results in a shift in the redox status of the cytoplasm to a more oxidative state, and purifying the expressed peptide [see Abstract; p. 3-4].
With respect to claim 18, Oganesyan et al. teach the method wherein the protein expressed is CRM197 peptide, which is a diphtheria toxin [see p. 2, lines 3-10].
With respect to claim 19, Oganesyan et al. teach the method wherein the recombinant cell has a reduced activity of only one disulfide reductase enzyme [see p. 3].
With respect to claim 20, Oganesyan et al. teach the method wherein the recombinant cell has a reduced activity of more than one disulfide reductase enzyme [see p. 3].
With respect to claim 21, Oganesyan et al. teach the method wherein the one or more disulfide reductase enzymes comprises one or more of an oxidoreductase, a dihydrofolate reductase, a thioredoxin reductase, or a glutathione reductase [see p. 4, lines 12-15].
With respect to claim 22, Oganesyan et al. teach the method wherein the recombinant cell is an E. coli cell [see p. 4, lines 11-12].
With respect to claim 23, Oganesyan et al. teach the method wherein the expression vector comprises one or more inducible promoters [see p. 4, lines 3-24; p. 7, bottom; p. 12].
With respect to claim 24, Oganesyan et al. teach the method wherein the expression vector contains expressible sequences, an inducible first promoter and expressing the protein comprises inducing the inducible first promoter with a first inducing agent, the gene contains an inducible second promoter and inducing with a second inducing agent, wherein the first and second inducing agents are the same [see 4, lines 3-24; p. 7, bottom; p. 11, bottom bridging to p. 12].
With respect to claim 25, Oganesyan et al. teach the method wherein the isolating comprises chromatography [see p. 4, lines 25-27].
With respect to claim 26, Oganesyan et al. teach the method wherein the chromatography comprises a dextran sulfate resin, an active sulfate resin, a phosphate resin, a heparin resin, or a heparin-like resin [see p. 4, lines 25-27].
With respect to claim 27, Oganesyan et al. teach the method further comprising conjugating the isolated protein with a chemical compound [see p. 4, bottom; p. 14, lines 22-24].
With respect to claim 28, Oganesyan et al. teach the method wherein the chemical compound comprises a polysaccharide, protein, peptides, oligosaccharides and haptens [see p. 14, lines 22-24].
With respect to claim 29, Oganesyan et al. teach the method wherein the reducing activity results in a shift in the redox status of the cytoplasm to a more oxidative state (interpreted as an oxidizing agent) [see Abstract; p. 3-4].
With respect to claim 31, Oganesyan et al. teach a method of producing a CRM peptide from E. coli comprising expressing the protein from an E. coli (interpreted as containing a genome) containing an expression vector that encodes the peptide sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, wherein the reducing activity results in a shift in the redox status of the cytoplasm to a more oxidative state, and purifying the expressed peptide from the cytoplasm [see Abstract; p. 3-4, p. 7]. Oganesyan et al. teach wherein CRM contains two disulfide bonds that are important for correct folding, function and solubility [see p. 7].
With respect to claim 46, Oganesyan et al. teach a method for producing a soluble CRM197 protein from E. coli comprising expressing the protein from an E. coli (interpreted as containing a genome) containing an expression vector that encodes the protein sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, and purifying the expressed protein [see Abstract; p. 3]. Oganesyan et al. teach the method wherein the recombinant E. coli comprises a gor mutation [see Abstract; p. 3-4; p. 7; p. 9].
With respect to claim 50, Oganesyan et al. teach the method wherein the recombinant cell is an E. coli cell [see p. 4, lines 11-12].
However, Oganesyan et al. does not teach the methods of claims 1-28, 31, and 46 of expressing a peptidase from a gene in the recombinant cell, wherein the peptidase removes the methionine from the N-terminus of the protein or peptide expressed; the method of claims 7 and 49, wherein the peptidase comprises a methionine aminopeptidase; and the method of claims 12, 17, and 48, wherein the peptidase gene is integrated into the genome of the recombinant cell.
Norby et al. teach that production of peptides by recombinant techniques using either prokaryotic or eukaryotic systems inherently yields the peptide with a leading methionine amino acid residue that may not be present in the native protein [see paragraph 0003]. Norby et al. teach a method of producing a peptide comprising expressing the peptide in a recombinant cell, wherein the expressed peptide contains an N-terminal methionine, and the recombinant cell contains a gene that encodes a peptidase; expressing the peptidase gene such that the N-terminal methionine is cleaved from the expressed peptide; and isolating the peptide [see Abstract; paragraphs 0006-0011; 0051-0062]. Norby et al. further teach the method wherein the peptidase gene and peptide gene is integrated into the genome of the recombinant cell [see paragraphs 0051-0062].
With respect to claim 47, Norby et al. teach the method wherein the peptide is expressed from another gene that is integrated into the genome of the recombinant cell [see paragraphs 0051-0062].
With respect to claim 48, Norby et al. teach the method wherein the peptidase gene is integrated into the genome of the recombinant cell [see paragraphs 0051-0062].
With respect to claim 49, Norby et al. teach the method wherein the peptidase is a methionine amino peptidase [see paragraphs 0051-0062].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Oganesyan et al. and Norby et al. according to the teachings of Norby et al. to include a methionine aminopeptidase in the recombinant cell of Oganesyan et al. because Oganesyan et al. teach methods for producing high quantities of soluble CRM proteins and peptides by reducing the activity of disulfide reductase activity in an E. coli cell. Norby et al. teach that production of peptides by recombinant techniques using either prokaryotic or eukaryotic systems inherently yields the peptide with a leading methionine amino acid residue that may not be present in the native protein and teach coexpressing a methionine aminopeptidase with a protein in order to cleave the initiator methionine. One of ordinary skill in the art desiring to produce a soluble protein in its native form would look to combine the teachings of Oganesyan et al. and Norby et al. with a reasonable expectation of success and a reasonable level of predictability because Norby et al. acknowledges that coexpressing a methionine aminopeptidase with a protein of interest can result in processing and removal of the initiator methionine. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 10 of applicants’ remarks, applicants contend that the combination of references does not disclose the combination of integrating an aminopeptidase into an E. coli cell that has reduced activity for disulfide reductase.
This argument is found to be not persuasive because as stated above, Oganesyan et al. teach methods for producing high quantities of soluble CRM proteins and peptides by reducing the activity of disulfide reductase activity in an E. coli cell. Norby et al. teach that production of peptides by recombinant techniques using either prokaryotic or eukaryotic systems inherently yields the peptide with a leading methionine amino acid residue that may not be present in the native protein and teach coexpressing a methionine aminopeptidase with a protein in order to cleave the initiator methionine. MPEP 2143 states “[t]he Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.” “Exemplary rationales that may support a conclusion of obviousness is ‘combining prior art elements according to known methods to yield predictable results’”. In the instant case, the reduction of disulfide reductase activity in E. coli cells for recombinant protein production was already known in the art as taught by Oganesyan et al. and expression of methionine amino peptidase in E. coli to cleave the initiator methionine off recombinantly expressed proteins was already known in the art as taught by Norby et al. As such, one of ordinary skill in the art would have a reasonable expectation of success and predictability to combine the two elements taught by Oganesyan et al. and Norby et al.
22. The rejection of claim 30 under 35 U.S.C. 103 as being unpatentable over Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) as applied to claims 1-29 and 31 above, and further in view of Thom et al. (Bioconjugate Chemistry, 2011; cited on PTO-892 mailed on 08/22/2025) 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.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) as applied to claims 1-29, 31, and 46-50 above, and further in view of Thom et al. (Bioconjugate Chemistry, 2011; cited on PTO-892 mailed on 08/22/2025).
23. The relevant teachings of Oganesyan et al. and Norby et al. as applied to claims 1-29, 31, and 46-50 are set forth above.
With respect to claim 30, Oganesyan et al. teach the method of producing a CRM peptide from E. coli comprising expressing the protein from an E. coli (interpreted as containing a genome) containing an expression vector that encodes the peptide sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, wherein the reducing activity results in a shift in the redox status of the cytoplasm to a more oxidative state, and purifying the expressed peptide from the cytoplasm [see Abstract; p. 3-4, p. 7]. Oganesyan et al. teach wherein CRM contains two disulfide bonds that are important for correct folding, function and solubility [see p. 7]. , Oganesyan et al. further teach conjugating the isolated protein with a chemical compound, wherein the chemical compound comprises a polysaccharide, protein, peptides, oligosaccharides and haptens for vaccines [see p. 4; p. 14, lines 22-24].
However, the combination of Oganesyan et al. and Norby et al. do not each the method of claim 30, wherein the oxidizing agent comprises a hydrazide, a hydrazine, an aminoxy group, N-terminal 1-amino, 2-alcohol amino acid, or a combination thereof.
Thom et al. teach that recombinant protein therapeutics have emerged as effective treatment for a variety of conditions and teach that the covalent attachment of PEG to a therapeutic protein increasing the half-life of the protein in vivo by decreasing renal clearance [see p. 1017, column 1]. Thom et al. further teach that PEGylation of a target protein can improve its solubility and stability [see p. 1017, column 1]. Thom et al. teach a method for site specific C-terminal PEGylation of recombinant proteins that exploits the chemical cleavage of intein-fusion proteins with hydrazine to directly produce recombinant protein hydrazides that permits the site-specific C-terminal modification by hydrazone-forming ligation reactions [see Abstract].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Oganesyan et al., Norby et al. and Thom et al. according to the teachings of Thom et al. to use an oxidizing agent such as hydrazine to conjugate a PEG molecule to the peptides of Oganesyan et al. and Norby et al. because Oganesyan et al. and Norby et al. teach methods for production of high amounts of soluble proteins for therapeutic purposes. Thom et al. teach a method for site specific C-terminal PEGylation of recombinant proteins that exploits the chemical cleavage of intein-fusion proteins with hydrazine to directly produce recombinant protein hydrazides. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would have been motivated to combine the teachings of Oganesyan et al., Norby et al. and Thom et al. because Thom et al. acknowledges that the covalent attachment of PEG to a therapeutic protein increasing the half-life of the protein and solubility. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 10 of applicants’ remarks, applicants contend that none of the use of oxidizing agents is disclosed in the combination of Oganesyan, Norby and Thom.
This argument is found to be not persuasive for the reasons already set forth above.
24. Claims 33-35 and 37-40 are newly rejected under 35 U.S.C. 103 as being unpatentable over Peters et al. (US Patent Application Publication 2013/0281671 A1; cited on PTO-892 mailed on 08/22/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023). This new grounds of rejection is necessitated by applicants’ amendment to the claims to cancel claim 36 and insert said limitations into claim 33.
25. As amended, claims 33-35 and 37-40 are drawn to a method of producing a protein comprising: expressing a preprotein in a recombinant cell which contains a recombinantly engineered protease gene containing a translation induction sequence, wherein the protease gene is integrated into the genome of the recombinant cell and encodes a methionine aminopeptidase; inducing expression of the protease gene such that the preprotein is cleaved to form the protein; and harvesting the protein.
26. With respect to claim 33, Peters et al. teach a method of producing a preprotein, Factor VIII, comprising co-transfecting a host cell with a polynucleotide encoding Factor VIII and a polynucleotide encoding a protein convertase, inducing (translation induction sequence) expression of Factor VIII and proprotein convertase, wherein the proprotein convertase cleaves the Factor VIII to produce a processed Factor VIII, and isolate the processed Factor VIII [see Abstract; paragraphs 0004-0022; 0035-0037].
With respect to claim 34, Peters et al. teach the method wherein the preprotein is Factor VIII (interpreted as proprotein of the coagulation system) [see Abstract; paragraphs 0004-0022; 0035-0037].
With respect to claim 35, Peters et al. teach the method wherein the vector is a viral vector or plasmid vector designed to integrate the nucleotide sequence encoding the protease into the genome of the host cell [see paragraphs 0129-0134].
With respect to claims 37-40, Peters et al. teach a method of producing a preprotein, Factor VIII, comprising co-transfecting a host cell with a polynucleotide encoding Factor VIII and a polynucleotide encoding a protein convertase, inducing (translation induction sequence) expression of Factor VIII and proprotein convertase, wherein the proprotein convertase cleaves the Factor VIII to produce a processed Factor VIII, and isolate the processed Factor VIII [see Abstract; paragraphs 0004-0022; 0035-0037]. Peters et al. teach the method wherein the preprotein is Factor VIII (interpreted as proprotein of the coagulation system) [see Abstract; paragraphs 0004-0022; 0035-0037] and wherein the vector is a viral vector or plasmid vector designed to integrate the nucleotide sequence encoding the protease into the genome of the host cell under control of inducible promoters and enhancer sequences [see paragraphs 0127-0134].
However, Peters et al. does not teach the method of claims 33-40, wherein a methionine aminopeptidase gene is integrated into the genome of the recombinant cell and the method of claim 37, wherein expression of the methionine aminopeptidase gene removes an N-terminal methionine from the preprotein or the protein.
Norby et al. teach that production of peptides by recombinant techniques using either prokaryotic or eukaryotic systems inherently yields the peptide with a leading methionine amino acid residue that may not be present in the native protein [see paragraph 0003]. Norby et al. teach a method of producing a peptide comprising expressing the peptide in a recombinant cell, wherein the expressed peptide contains an N-terminal methionine, and the recombinant cell contains a gene that encodes a peptidase; expressing the peptidase gene such that the N-terminal methionine is cleaved from the expressed peptide; and isolating the peptide [see Abstract; paragraphs 0006-0011; 0051-0062]. Norby et al. further teach the method wherein the peptidase gene and peptide gene is integrated into the genome of the recombinant cell [see paragraphs 0051-0062].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Peters et al. and Norby et al. according to the teachings of Norby et al. to include a methionine aminopeptidase in the recombinant cell of Peters et al. because Peters et al. teach methods for producing high quantities of processed Factor VIII proteins. Norby et al. teach that production of peptides by recombinant techniques using either prokaryotic or eukaryotic systems inherently yields the peptide with a leading methionine amino acid residue that may not be present in the native protein and teach coexpressing a methionine aminopeptidase with a protein in order to cleave the initiator methionine. One of ordinary skill in the art desiring to produce a soluble protein in its native form would look to combine the teachings of Peters et al. and Norby et al. with a reasonable expectation of success and a reasonable level of predictability because Norby et al. acknowledges that coexpressing a methionine aminopeptidase with a protein of interest can result in processing and removal of the initiator methionine. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Applicants’ remarks filed on 11/18/2025 have been fully considered by the examiner; however, they are rendered moot in view of the new rejection set forth above, which is necessitated by applicants’ amendment to the claims.
27. Claims 41-42 are newly rejected under 35 U.S.C. 103 as being unpatentable over Peters et al. (US Patent Application Publication 2013/0281671 A1; cited on PTO-892 mailed on 08/22/2025) in view of Norby et al. (US Patent Application Publication 2009/0253900 A1; cited on IDS filed on 08/24/2023) as applied to claims 33-35 and 37-40 above, and further in view of Oganesyan et al. (WO 2015/117093 A1; cited on IDS filed on 03/10/2025). This new grounds of rejection is necessitated by applicants’ amendment to the claims to cancel claim 36 and insert said limitations into claim 33.
28. The relevant teachings of Peters et al. and Norby et al. as applied to claims 33-35 and 37-40 are set forth above.
With respect to claims 41-42, Peters et al. teach a method of producing a preprotein, Factor VIII, comprising co-transfecting a host cell such as a prokaryotic cell with a polynucleotide encoding Factor VIII and a polynucleotide encoding a protein convertase, inducing (translation induction sequence) expression of Factor VIII and proprotein convertase, wherein the proprotein convertase cleaves the Factor VIII to produce a processed Factor VIII, and isolate the processed Factor VIII [see Abstract; paragraphs 0004-0022; 0035-0037; 0139]. Peters et al. teach the method wherein the preprotein is Factor VIII (interpreted as proprotein of the coagulation system) [see Abstract; paragraphs 0004-0022; 0035-0037] and wherein the vector is a viral vector or plasmid vector designed to integrate the nucleotide sequence encoding the protease into the genome of the host cell under control of inducible promoters and enhancer sequences [see paragraphs 0127-0134]. Peters et al. also teach the expression of Factor VIII as a fusion protein in complex with a an Fc domain comprising disulfides [see paragraphs 0052-0054; 0071].
However, the combination of Peters et al. and Norby et al. do not teach the method of claim 41, wherein the recombinant cell has a reduced activity of one or more disulfide reductase enzymes and the method of claim 42, wherein the recombinant cell is E. coli that contains a gor mutation.
Oganesyan et al. teach the method of producing a CRM peptide from E. coli comprising expressing the protein from an E. coli having a gor mutation containing an expression vector that encodes the peptide sequence, wherein the recombinant cell has a mutation in one or more disulfide reductase genes such that the activity is reduced, wherein the reducing activity results in a shift in the redox status of the cytoplasm to a more oxidative state, and purifying the expressed peptide from the cytoplasm [see Abstract; p. 3-4, p. 7; p. 9]. Oganesyan et al. teach increasing the oxidative state of the cell by reducing the disulfide reductase activity increases the solubility of the expressed protein and overcomes the need to refold the proteins from inclusion bodies [see p. 3].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Peters et al., Norby et al. and Oganesyan et al. according to the teachings of Oganesyan et al. to include a host cell with reduced disulfide reductase activity in the methods of Peters et al. and Norby et al. because Peters et al. and Norby et al. teach methods for the production of Factor VIII by coexpressing the protein with a protease to cleave Factor VIII into its final form for therapeutic purposes. Oganesyan et al. teach that increasing the oxidative state of the cell by reducing the disulfide reductase activity increases the solubility of the expressed recombinant proteins and overcomes the need to refold the proteins from inclusion bodies. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would have been motivated to combine the teachings of Peters et al., Norby et al. and Oganesyan et al. because Oganesyan et al. acknowledges that increasing the oxidative state of the cell by reducing the disulfide reductase activity increases the solubility of the expressed recombinant proteins and overcomes the need to refold the proteins from inclusion bodies. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Applicants’ remarks filed on 11/18/2025 have been fully considered by the examiner; however, they are rendered moot in view of the new rejection set forth above, which is necessitated by applicants’ amendment to the claims.
Conclusion
29. Status of the claims:
Claims 1-31, 33-35, 37-42, and 46-50 are pending.
Claims 1-31, 33-35, 37-42, and 46-50 are rejected.
No claims are in condition for an allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656