DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amendment filed on 01/06/2026 amended claims 1, 2, 4, 6, 8, 9, 11, 13, and 15, cancelled claims 14 and 16, and added new claims 17-22. Claims 1-13, 15, and 17-22 are pending and will be examined on the merits.
Response to Amendment
The amendment filed 01/06/2026 in response to the office action mailed 08/06/2025 is acknowledged. The claim objections and the rejections set forth under 35 USC 112 and 101 are withdrawn for the following reasons:
Applicant’s amendments to the claims have overcome the rejection under 112(b) regarding the improper Markush grouping of claims 1-16, the use claim rejections under 112(b) and 101 for claims 14-16, and the 112(b) rejections for ‘preferably’ recited in claims 4, 6, 11, and 13.
New rejections are set forth below.
Claim Objections
Claims 2 and 9 are objected to because of the following informalities: Examiner suggests amending claims 2 and 9 to recite positions in a SEQ ID NO, not on a Genbank chromosome sequence, to better align with standard patent language. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 2 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 2 recites the yeast cell of claim 1, wherein “the genetic modification in the endogenous gene of SRB8 is a mutation at position 949930 on chromosome 1, wherein the genetic modification in the endogenous gene ALG9 is a mutational position 65654 on chromosome 2, wherein the genetic modification in the endogenous gene ACIB2EUKG772803 is a mutation at position 1303485 on chromosome 4, wherein the genetic modification in the endogenous gene KAP123 is a mutation at position 1323758 on chromosome 1, or wherein the genetic modification in the endogenous gene FLO400 is a mutation at position 1491140 on chromosome 4.” Claim 1 recites that the genetic modification of ALG9, SRB8, ACIB2EUKG772803, KAP 123, or FLO400 must be an inactivating modification.
The instant specification provides a definition for “a genetic modification” as “any change within a nucleotide sequence which results in the addition, deletion, or alteration, specifically substitution, of at least one nucleotide. Specifically, the genetic modification may be any a mutation, insertion or deletion, or any combination thereof” in paragraph [0092]. A definition for “inactivating mutation” is provided in paragraph [0093] as a loss of function mutation, which results in the gene product having less or no function, or in no gene product being produced. Paragraph [0096] provides a definition for “a mutation”, reciting “Specifically, a mutation is a point mutation, which is herein understood as a mutation to alter one or more (but only a few) contiguous nucleotides or amino acids, e.g. l, or 2, or 3 nucleotides or amino acids are substituted, inserted or deleted at one position in an amino acid sequence. Amino acid substitutions may be conservative amino acid substitutions or non-conservative amino acid substitutions.” Accordingly, the language of claim 2, regarding, for example, the genetic modification in the endogenous gene of SRB8, indicates that the mutation at position 949930 on chromosome 1 may be any point mutation, or any change to the existing nucleotide, regardless of if it changes the encoded amino acid or not.
The instant specification provides the examples of disrupting gene expression via insertion of a plasmid in Examples 1, 3, and 4 (pages 43-44, 46) and a frameshift mutation in Example 2 (page 45). Therefore, the instant specification does not provide any examples of an inactivating mutation comprising a single point mutation in any of the claimed genes or at any of the claimed positions. As is known in the art, some point mutations can be synonymous; i.e., encode the same amino acid. Additionally, a point mutation that is non synonymous, or that changes the amino acid, could be conservative or non-conservative. Conservative mutations are generally considered less likely to affect protein folding and function. As the instant specification does not provide any guidance on what point mutations may lead to inactivation of the gene product and which will be conservative, there is not sufficient written description support for claim 2 as written.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
While conservative vs non-conservative amino acid substitutions are generally known in the art (as listed in the instant specification, paragraphs [0062]-[0064] and [0093]), there is an unpredictability to protein structure, folding, and function that does not reasonably allow one of ordinary skill in the art to automatically understand what amino acid substitutions will preserve or disrupt the function of proteins. Gromiha et al. (Biochemical Society Transactions (2007) 35(6), 1569-1573) describe the complicated interactions that influence protein folding and stability, and describe algorithms that can predict protein stability, but not with 100% accuracy. Rajasekaran et al. (Biochemistry (2017) 56(1), 294-305) have more recently investigated the role of crucial amino acid residues in protein folding, disclosing that even minor disturbances can influence distal residue interactions (see page 301, first paragraph right column). Kulandaisamy et al. (International Journal of Biological Macromolecules (2017) 94, 438-444) disclose that most residues in a protein are heavily involved in folding and stability, and thus mutation of any residue can have effects on protein function (page 443, left column, second paragraph). Moreover, Skolnick et al. (Trends in Biotechnology (2000) 18:34-39) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Taken together, one of ordinary skill in the art would understand that it is impossible to state that any mutation to a protein would result in a guaranteed results, in this case, inactivation.
Overall, based on the disclosure, the state of the art at the time of filing, a skilled artesian would have recognized that the applicant was not in possession of the claimed invention at the time of filing. Any mutation occurring at one of the named positions in claim 2 is not guaranteed to be an inactivating mutation. Consequently, claim 2 does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant is reminded that Vas- Cath makes clear that the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 9 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.
Claims 2 and 9 recite the yeast cell of claim 1 or 8, respectively, wherein “the genetic modification in the endogenous gene of SRB8 is a mutation at position 949930 on chromosome 1, wherein the genetic modification in the endogenous gene ALG9 is a mutational position 65654 on chromosome 2, wherein the genetic modification in the endogenous gene ACIB2EUKG772803 is a mutation at position 1303485 on chromosome 4, wherein the genetic modification in the endogenous gene KAP123 is a mutation at position 1323758 on chromosome 1, or wherein the genetic modification in the endogenous gene FLO400 is a mutation at position 1491140 on chromosome 4.” The citation to a specific location on a chromosome makes this claim indefinite. The instant specification refers to the Genbank entries LT962476.1, LT962477.1, and LT962479.1. However, these entries refer to a specific version, which may not always be available to the public. Moreover, these Genbank entries are drawn to Komagataella phaffii strain CBS7435. Other strains of K. phaffii may have slightly different chromosomal sequences, and therefore a position in the chromosome of strain CBS7435 is not necessarily the same on every K. phaffii genome. Therefore, it is unclear if the mutations of claims 2 and 9 refer to any mutation at that specific location on a chromosome, or if one is expected to extrapolate to find the synonymous position on a different chromosome. To overcome this rejection while maintaining the subject matter of claims 2 and 9, Examiner suggests amending the claim to recite a SEQ ID NO.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-7, and 17 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2005/0170452 A1, Wildt et al., published 08/04/2005.
The instant claims are drawn to a genetically modified Komagataella phaffi (syn. Pichia pastoris, recited paragraph [0002] of instant specification) comprising a recombinant nucleic acid sequence for a protein of interest (POI) and an inactivating genetic modification to ALG9, SRB8, ACIB2EUKG772803, KAP123, or FLO400. The instant specification defines a protein of interest as “a protein that is produced by means of recombinant technology in a host cell” (paragraph [00103]) and a genetic modification as “any change within a nucleotide sequence which results in the addition, deletion, or alteration, specifically substitution, of at least one nucleotide. Specifically, the genetic modification may be any a mutation, insertion or deletion, or any combination thereof” (paragraph [0092]), and an inactive modification is defined in paragraph [0093] as a modification that results in the gene product having less or no function.
Wildt et al. teach a genetically modified P. pastoris with diminished or depleted activity of the enzyme encoded by the ALG9 gene in paragraph [0130], and in Example 3, paragraph [0234]. In Example 3, the ALG9 gene is replaced with a NAT resistance cassette. As the antibiotic resistance cassette NAT meets the limitations of the specification’s definition of a protein of interest (a protein produced by recombinant means), Wildt et al. meets the limitations of instant claim 1. Moreover, paragraph [0132] discloses a cell depleted for ARG9 activity that expresses, from a nucleic acid molecule introduced into the host cell, an enzyme such as alpha-mannosidase (see also example 4, paragraphs [0235-8]). Again, this cell reads on the invention of instant claim 1, as the mannosidase enzyme is considered a POI by the definition provided. Therefore, Wildt et al. anticipate the invention of instant claim 1.
As the yeast cell of Wildt et al. contained the ALG9 gene deleted via allelic replacement, the genetic modification of ALG9 meets the limitation of instant claim 3, and has a deletion of one or more bases, as well as instant claims 4 and 17, which recites that the deletion is at least 50% or 90%, respectively, of the gene. As the NAT resistance cassette can be interpreted as the POI, Wildt et al. also anticipates claim 5, which recites that the ALG9 gene is replaced by the POI, and instant claim 6, which specifies that the POI is contained on an expression cassette, which is defined in the specification as a DNA coding sequence (paragraph [00147]).
Finally, the yeast cell of Wildt et al. comprising the ALG9 mutation is used for the expression of human-like glycoproteins, as recited in Wildt et al. claim 1 and claim 8. Claim 22 recites that the method of expressing human-like glycoproteins further comprises isolating the glycoprotein from the host. Therefore, Wildt et al. disclose the method of claim 7, a method of producing a recombinant POI comprising the steps (a) providing a genetically modified yeast cell according to instant claim 1, (b) cultivating said cell to allow for expression of the POI, and (c) isolating the POI from the cells. Therefore, Wildt et al. anticipate instant claims 1, 3-7, and 17.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-8, 10-13, 15, and 17-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wildt et al. in view of WO 2018/0135551 A1, Lu et al., published 1/18/2018.
The instant claims are drawn to a genetically modified Komagataella phaffi (syn. Pichia pastoris, recited paragraph [0002] of instant specification) comprising a recombinant nucleic acid sequence for a protein of interest (POI) and an inactivating genetic modification to ALG9, SRB8, ACIB2EUKG772803, KAP123, or FLO400. The instant specification defines a protein of interest as “a protein that is produced by means of recombinant technology in a host cell” (paragraph [00103]) and a genetic modification as “any change within a nucleotide sequence which results in the addition, deletion, or alteration, specifically substitution, of at least one nucleotide. Specifically, the genetic modification may be any a mutation, insertion or deletion, or any combination thereof” (paragraph [0092]), and an inactive modification is defined in paragraph [0093] as a modification that results in the gene product having less or no function.
Wildt et al. teach a genetically modified P. pastoris with diminished or depleted activity of the enzyme encoded by the ALG9 gene in paragraph [0130], and in Example 3, paragraph [0234]. In Example 3, the ALG9 gene is replaced with a NAT resistance cassette. As the antibiotic resistance cassette NAT meets the limitations of the specification’s definition of a protein of interest (a protein produced by recombinant means), Wildt et al. meets the limitations of instant claim 1. Moreover, paragraph [0132] discloses a cell depleted for ARG9 activity that expresses, from a nucleic acid molecule introduced into the host cell, an enzyme such as alpha-mannosidase (see also example 4, paragraphs [0235-8]). Again, this cell reads on the invention of instant claim 1, as the mannosidase enzyme is considered a POI by the definition provided. Therefore, Wildt et al. teach the invention of instant claim 1.
As the yeast cell of Wildt et al. contained the ALG9 gene deleted via allelic replacement, the genetic modification of ALG9 meets the limitation of instant claim 3, and has a deletion of one or more bases, as well as instant claim 4, which recites that the deletion is at least 50% of the gene. As the NAT resistance cassette can be interpreted as the POI, Wildt et al. also teaches instant claim 5, which recites that the ALG9 gene is replaced by the POI, and instant claim 6, which specifies that the POI is contained on an expression cassette, which is defined in the specification as a DNA coding sequence (paragraph [00147]).
Finally, the yeast cell of Wildt et al. comprising the ALG9 mutation is used for the expression of human-like glycoproteins, as recited in Wildt et al. claim 1 and claim 8. Claim 22 recites that the method of expressing human-like glycoproteins further comprises isolating the glycoprotein from the host. Therefore, Wildt et al. disclose the method of claim 7, a method of producing a recombinant POI comprising the steps (a) providing a genetically modified yeast cell according to instant claim 1, (b) cultivating said cell to allow for expression of the POI, and (c) isolating the POI from the cells. Therefore, Wildt et al. teach instant claims 1 and 2-7.
Wildt et al. do not teach a genetically modified P. pastoris for expression of a variety of POIs comprising in its genome (a) a landing pad comprising an empty expression cassette comprising target sequences for homologous recombination and (b) a genetic modification in ALG9, as recited in instant claim 8, or where the landing pad is inserted into the modified gene ALG9, as in instant claim 12.
Conclusion
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 Amelia Stephens whose telephone number is (571)272-1006. The examiner can normally be reached M-F 8-5 EST.
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/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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