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 .
Claim status
In this prosecution, examiner is pursuing the amended claims filed 06 January 2026, where claims 1-26 are pending.
Election/Restrictions
Applicant’s election without traverse of Group 1, Claims 1-19, drawn to a method of expressing a protein of interest from a mammalian cell culture process in the reply filed on 06 January 2026 is acknowledged.
Claims 20-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-19 are herein under examination.
Priority
This application was filed 04/28/2023 and is a 371 application of PCT/US21/57606 filed on 11/01/2021, which claims benefit to the Provisional Application 63108084 filed on 10/30/2020. Thus, the earliest possible priority for the instant application is 10/30/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/03/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and the signed and initialed PTO Forms 1449 are mailed with this action.
Abstract Objection
The abstract of the disclosure filed 04/28/2023 is objected to because the abstract is only 32 words in length. Therefore, submitted abstract is considered non-compliant.
Applicant is reminded of the proper language and format for an abstract of the disclosure. MPEP §608.01(b) states that the abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Therefore, appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18-19, is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 and 19 is recited “formulated” in a pharmaceutically acceptable formulation and “formulated” protein of interest. The term “formulated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear that “how the protein of interest will be formulated in a pharmaceutically acceptable formulation?” See MPEP 2173.05(b).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-6, 11-13, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Faust et al. (EP3441471A1; published on Feb. 13 2019; cited in IDS filed 09/03/2025; hereinafter “Faust”).
With respect to claims 1 and 15, Faust discloses method of expressing one or more protein(s) of interest (POIs) from a mammalian cell culture process, the method comprising culturing a mammalian cell (i.e., CHO cells) in a cell culture media, wherein the mammalian cell comprises a nucleic acid encoding an insulin-like growth factor receptor 1 (IGFlR) mutant (i.e, CD8-IGF1R) that is constitutively active and further comprises a heterologous nucleic acid encoding the protein of interest (claims 1-4 of Faust).
Regarding claims 2 and 3, Faust discloses the methods of the present invention, the cell line is cultivated in a cell culture medium either not containing the growth factor that is recognized by said growth factor receptor or containing said growth factor at concentrations which are too low to support growth of the cells in the absence of expression of said constitutively active variant of a growth factor receptor. In this context, respective concentrations which are too low in this respect depend on the specific growth factor and growth factor receptor and can be easily determined by the person skilled in the art ([0021] of Faust). Therefore, Faust anticipates that instant claim limitation of claims 2-3.
Regarding claim 4, Faust discloses that the IGF1R mutant is encoded by a nucleic acid which is stably integrated into the mammalian cell genome ([0010] of Faust).
Regarding claim 5, Faust discloses that the stable producer cell lines (such as CAP – human amniocyte-derived suspension cells, CHO cell etc.) expressing one or more protein(s) of interest (POIs), comprising the stable transfection of cells with a gene encoding a constitutively active variant of a growth factor receptor. The recombinant expression of human CD8-IGF1 R in CAP cells leads to constitutive activation of the human CD8-IGF1R and related downstream signaling pathways and this constitutive IGF1 R activation can compensate IGF1 starvation (IGF-1 depleted medium) and thereby allow for growth of CAP cells in IGF1-depleted cell culture medium ([0011], [0020], [0034] of Faust). The constitutively active variant of a growth factor receptor is a human CD8-IGF-1R fusion protein comprises or consists of the amino acid sequence of SEQ ID NO: 1 which is an edited endogenous IGF1R sequence (see the UCSC Genome Browser on Human alignment result).
Regarding claim 6, Faust discloses that the mammalian cell has a growth rate comparable to a mammalian cell of the same lineage without the IGF1R mutant in a cell culture media with 0.1 mg/L IGF-1 (e.g., IGF-1-depleted growth medium). ([0050] of Faust)
Regarding claims 11-12, Faust discloses that the protein of interest is an antigen binding protein (i.e, monoclonal antibodies) (claims 3-4 of Faust).
Regarding claim 13, Faust discloses that the wherein the mammalian cell culture process utilizes a fed-batch culture process ([0028] ¶ Figure 2, and [0050] of Faust).
Accordingly, Faust anticipates the instant claims 1-6, 11-13, and 15.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 10-15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Faust et al. (EP3441471A1; published on Feb. 13 2019; cited in IDS filed 09/03/2025; hereinafter “Faust”), in view of Kim et al., (Batch, fed‐batch, and microcarrier cultures with CHO cell lines in a pressure‐cycle driven miniaturized bioreactor. Biotechnology and bioengineering, 109(1), pp.137-145, 2012; cited in PTO892; hereinafter “Kim”).
With respect to claims 1 and 15, Faust discloses method of expressing one or more protein(s) of interest (POIs) from a mammalian cell culture process, the method comprising culturing a mammalian cell (i.e., CHO cells) in a cell culture media, wherein the mammalian cell comprises a nucleic acid encoding an insulin-like growth factor receptor 1 (IGFlR) mutant (i.e, CD8-IGF1R) that is constitutively active and further comprises a heterologous nucleic acid encoding the protein of interest (claims 1-4 of Faust).
Regarding claims 2 and 3, Faust discloses the methods of the present invention, the cell line is cultivated in a cell culture medium either not containing the growth factor that is recognized by said growth factor receptor or containing said growth factor at concentrations which are too low to support growth of the cells in the absence of expression of said constitutively active variant of a growth factor receptor. In this context, respective concentrations which are too low in this respect depend on the specific growth factor and growth factor receptor and can be easily determined by the person skilled in the art ([0021] of Faust). Therefore, Faust anticipates that instant claim limitation of claims 2-3.
Regarding claim 4, Faust discloses that the IGF1R mutant is encoded by a nucleic acid which is stably integrated into the mammalian cell genome ([0010] of Faust).
Regarding claim 5, Faust discloses that the stable producer cell lines (such as CAP – human amniocyte-derived suspension cells, CHO cell etc.) expressing one or more protein(s) of interest (POIs), comprising the stable transfection of cells with a gene encoding a constitutively active variant of a growth factor receptor. The recombinant expression of human CD8-IGF1 R in CAP cells leads to constitutive activation of the human CD8-IGF1R and related downstream signaling pathways and this constitutive IGF1 R activation can compensate IGF1 starvation (IGF-1 depleted medium) and thereby allow for growth of CAP cells in IGF1-depleted cell culture medium ([0011], [0020], [0034] of Faust). The constitutively active variant of a growth factor receptor is a human CD8-IGF-1R fusion protein comprises or consists of the amino acid sequence of SEQ ID NO: 1 which is an edited endogenous IGF1R sequence (see the UCSC Genome Browser on Human alignment result).
Regarding claim 6, Faust discloses that the mammalian cell has a growth rate comparable to a mammalian cell of the same lineage without the IGF1R mutant in a cell culture media with 0.1 mg/L IGF-1 (e.g., IGF-1-depleted growth medium). ([0050] of Faust)
With respect to claim 10, MPEP 2112.01 states that “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established,” In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). it is noted that the claimed wherein clauses do not recite any additional active method steps, but simply state a function, characterization or measurement of the results of product positively recited (e.g., yield of recombinant POIs). In here, Faust et al., suggest producing the instant claim recombinant protein (i.e., IGF1R) specifically, using same cell culture method, so the process of making the product would have been obvious. Accordingly, at the time of the invention POSITA would have obvious expectation that the titer of the expressed recombinant protein is 50 mg/Lat day 10 of the culture, and this limitations are not unexpected.
Regarding claims 11-12, Faust discloses that the protein of interest is an antigen binding protein (i.e., monoclonal antibodies) (claims 3-4 of Faust).
Regarding claim 13, Faust discloses that the mammalian cell culture process utilizes a fed-batch culture process ([0028] ¶ Figure 2, and [0050] of Faust).
Regarding claim 14, Faust discloses that the mammalian cell culture process utilizes a fed-batch culture process in a serum-free culture media with 0.03 mg/L or less IGF-1 (e.g., IGF-1-depleted growth medium) ([0027], [0028], [0037] ¶ Figure 2, and [0050] of Faust), however Faust is silent to the mammalian cell culture is established by inoculating a bioreactor of at least 100 L with at least 0.5 x 106 to 3.0 x 106 cells/mL. However, such was known in the prior art.
Kim teaches that the fed-batch bioreactors are the industry standard for cultivating Chinese Hamster Ovary (CHO) cells to produce therapeutic recombinant proteins. Kim reports the use of the miniaturized bioreactor for mammalian cell culture using an industrially important CHO cell line for batch, fed-batch, and microcarrier cultures. Kim concludes that the mini-bioreactor can be used for various types of suspension animal cell culture process development at densities and productivities relevant to industrial scale operation with at least 0.5 x 106 to 3.0 x 106 cells/mL (abstract, p. 138 “Materials and Methods” ¶ and p. 142 “Scale-Up Parameter Study” ¶).
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the cell culture method of Faust and include the bioreactor method as taught by Kim with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Kim because bioreactor provides a favorable cell culture environments; oxygen transfer coefficient and mixing time can be altered to mimic values in a larger scale system allowing for potential prediction of response during scale-up (abstract of Kim). The POSITA would have had a reasonable expectation of success in combining the teachings of Faust and Kim because each of these teachings both successfully culture the mammalian cell (i.e, CHO) that expressing the PIOs. Therefore, the products and method as taught by Faust et al. in view of Kim et al. would have been prima facie obvious over the products and method of the instant application.
Regarding claims 17-19, Faust discloses to compare the productivity of a CAP cell pool which was generated by conventional blasticidin selection and a CAP cell pool which was generated using the novel CD8-IGF1 R selection marker (See Fig. 2 and [0050] of Faust)). Although Faust does not disclose that the purified POIs are dissolved in a pharmaceutically acceptable formulation, however POSITA at the time of filing would anticipate to dissolve the isolated IGF1R in an appropriate buffer (i.e., pharmaceutically acceptable (e.g., Tris-HCl, PBS)).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Faust et al. (EP3441471A1; published on Feb. 13 2019; cited in IDS filed 09/03/2025; hereinafter “Faust”), in view of Kim et al., (Biotechnology and bioengineering, 109(1), pp.137-145, 2012; cited in PTO892; hereinafter “Kim”) as applied to claims 1-6, 10-15, and 17-19 above, and further in view of Mensah et al. (Establishment of DHFR-deficient HEK293 cells for high yield of therapeutic glycoproteins. Journal of bioscience and bioengineering, 128(4), pp.487-494, 2019; cited in PTO892; hereinafter “Mensah”).
As discussed previously, Faust discloses method of expressing one or more protein(s) of interest (POIs) from a mammalian cell culture process, the method comprising culturing a mammalian cell (i.e., CHO cells) in a cell culture media, wherein the mammalian cell comprises a nucleic acid encoding an insulin-like growth factor receptor 1 (IGFlR) mutant (i.e, CD8-IGF1R) that is constitutively active and further comprises a heterologous nucleic acid encoding the protein of interest (claims 1-4 of Faust).
Although regarding claim 16, Faust discloses the mammalian cell are CHO, however Faust silents to CHO cells are deficient in dihydrofolate reductase (DHFR). However, such was known in the prior art.
Mensah teaches that the use of protein therapeutics is effective for treating intractable human diseases, and the Chinese hamster ovary (CHO) cell lines are the most commonly used host cell expression system for recombinant protein production. High productive and stable clonal cell lines for recombinant protein production have been established from the DHFR-deficient CHO cell using the dihydrofolate reductase/methotrexate (DHFR/MTX) selection methods (abstract of Mensah).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to practice the cell culture method of Faust and substitute with DHFR deficient CHO cells as taught by Mensah with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Mensah because DHFR-deficient CHO cells can dramatically increase in the two protein expressions therefore, the higher yield production of several recombinant proteins including therapeutic proteins can be achieved (abstract of Mensah). The POSITA would have had a reasonable expectation of success in combining the teachings of Faust and Mensah because each of these teachings both successfully culture the mammalian cell (i.e, CHO) for the manufacturing recombinant protein therapeutics. Therefore, the products and method as taught by Faust et al. in view of Mensah et al. would have been prima facie obvious over the products and method of the instant application.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Subject matter free of art
Claim 7-9 are objected because art does not teach or reasonably suggest the SEQ ID NO: 1-4 (see ABSS report filed Jan. 23 2026). Since claims 7-9 depend from rejected base independent claim 1, accordingly, claims 7-9 are likewise objected. Claim 1 would be free of the art, if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684