Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Priority
Acknowledgement is made of Applicant’s claimed domestic priority under 35 U.S.C. § 119(e), of U.S. Provisional Application Serial No. 63/086,702 filed 10/02/2020.
Status of the Claims
The amendment dated 03/31/2023 is acknowledged. Claims 1-3, 5, 8, 10-11, 14-16, 23,31, 33, 35-36, 38-41 and 44 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/01/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Claim Objections
Claims 41 and 44 are objected to for the following informalities:
Claim 41 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 44, recites a process for producing the composition of claim 1,
According to the MPEP (2113), PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009).
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.
Claim 44 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 44 recites “according to claim 42”. There is insufficient antecedent basis for this limitation in the claim. Accordingly, one of ordinary skill in the art would not know the metes and bounds of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-3, 5, 8, 10-11, 14-16, 23, 31, 33, 35-36 and 38-40 are rejected under 35 U.S.C. 103(a) as being unpatentable over Baudoux et al. “Baudoux” (WO2009/079796, IDS of record dated 03/01/2024) in view of Gagnon et al. “Gagnon” (Biotechnology and Bioengineering, 2011, 108(6):1328-1337, IDS of record dated 03/01/2024) and further in view of Drapeau (WO2004/104186 IDS of record dated 03/01/2024).
The claims are directed to a method for producing an RSV F protein trimer in a fed batch cell culture, said method comprising the steps of: (i) providing mammalian cells that contain a gene encoding an RSV F protein in a cell culture medium to start a cell culture, and, (ii) culturing the cells at a temperature between about 33.0°C and 35.0°C, and (iii) providing glucose in a restricted manner to the cell culture by feeding glucose to the cell culture in response to rise of pH above a predetermined pH value.
Regarding claims 1, 2, 23, 31, 33 and 35-36, Baudoux discloses producing recombinant syncytial virus (RSV) antigens, particularly, recombinant F protein that has been modified to stabilize the trimeric prefusion conformation (paragraph [007]) that exhibit superior immunogenicity, and are particularly favorably employed as components of immunogenic compositions (e.g. vaccines) for protection against RSV infection and/or disease. Also disclosed are nucleic acids that encode the recombinant antigens, immunogenic composition containing the antigens, and methods for producing and using the antigens (paragraph [007]) pages 52-53 (Example 2: Production and Purification of PreF recombinant protein from CHO cells) and claims 2, 45, 77-78, 86-87 of Baudoux) (instant claims 23, 31, 33 and 35-36).
Baudoux does not explicitly teach the cells are cultured at a temperature between 33oC and 35oC nor the glucose is provided in a restricted manner to the cell culture by feeding glucose to the cell culture in response to rise of pH above a predetermined pH value.
Gagnon, however (as it pertains to the glucose being provided in a restricted manner to the cell culture in response to rise of pH) discloses “a simple method for control of lactate accumulation in suspension cultures of Chinese hamster ovary (CHO) cells based on the culture's pH was developed. When glucose levels in culture reach a low level (generally below 1 mM) cells begin to take up lactic acid from the culture medium resulting in a rise in pH. A nutrient feeding method has been optimized which delivers a concentrated glucose solution triggered by rising pH. We have shown that this high-end pH-controlled delivery of glucose can dramatically reduce or eliminate the accumulation of lactate during the growth phase of a fed-batch CHO cell culture at both bench scale and large scale (2,500 L). This method has proven applicable to the majority of CHO cell lines producing monoclonal antibodies and other therapeutic proteins. Using this technology to enhance a 12-day fed-batch process that already incorporated very high initial cell densities and highly concentrated medium and feeds resulted in an approximate doubling of the final titers for eight cell lines” (Abstract) whereby the CHO cell culture temperature was conducted at 37oC or 31oC (page 1329 first column). Further, Gagnon discloses “In the present work, we describe a method for very effective suppression of lactate accumulation during the growth phase of fed-batch cultures of CHO cells. The method is simple, scalable, requires no significant capital outlay at the largescale, and can result in dramatic increases in peak and sustained cell densities, cell viabilities, and overall bioreactor productivities. The method has been given the convenient acronym HIPDOG (HI-end pH-controlled Delivery Of Glucose)” (page 1329 first column first Para.).
With respect to culturing the cells at a temperature between about 33oC and 35oC, Gagnon discloses producing recombinant RSV F protein as a prefusion trimer at 37oC and “a nutrient feeding method has been optimized which delivers a concentrated glucose solution triggered by rising pH. We have shown that this high-end pH-controlled delivery of glucose can dramatically reduce or eliminate the accumulation of lactate during the growth phase of a fed-batch CHO cell culture at both bench scale and large scale (2,500 L) (Abstract). Furthermore, Drapeau discloses restricted glucose feed for animal cell culture whereby recombinant protein production is increased (Abstract) and states “as such, adjustment of the concentrations of such nutrients or agents in the base inoculation and feed media are routine in the art. Furthermore, a skilled artisan will recognize at what temperature and concentration a particular cell should be cultured” (paragraph [0043]). Thus, in the absence of any unexpected results, the temperature selection defined in the instant claim therein only can be seen as an arbitrary selection which does not involve an inventive step in view of Gagnon and Drapeau. Moreover, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. According to section 2144.05 of the M.P.E.P., "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980) (instant claims 1 and 2).
Accordingly, it would have been obvious to one of ordinary skill in the art to generate a method for producing an RSV F protein trimer in a fed batch cell culture as taught by Baudoux at various temperatures known in the art, whereby the glucose is provided in a restricted manner to the cell culture by feeding glucose to the cell culture in response to rise of pH above a predetermined pH value as disclosed by Gagnon. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the fact that Baudoux discloses recombinant RSV F proteins can be produced at high titers in a stabilized trimer prefusion conformation in CHO cells that exhibit superior immunogenicity, and are particularly favorably employed as components of immunogenic compositions (e.g. vaccines) for protection against RSV infection and/or disease (paragraph [007]); and given the knowledge that Gagnon discloses “In the present work, we describe a method for very effective suppression of lactate accumulation during the growth phase of fed-batch cultures of CHO cells. The method is simple, scalable, requires no significant capital outlay at the largescale, and can result in dramatic increases in peak and sustained cell densities, cell viabilities, and overall bioreactor productivities. The method has been given the convenient acronym HIPDOG (HI-end pH-controlled Delivery Of Glucose)” (page 1329 first column first Para.) with temperatures at 37oC or 31oC (page 1329 first column); and given the knowledge as disclosed by Drapeau that it is considered routine in the art to determine at what temperature and concentration a particular cell should be cultured” (paragraph [0043]). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 3, Baudoux in view of Gagnon and further in view of Drapeau, Gagnon discloses culturing the cells at a lower temperature between 30oC and 32oC (page 1329 first column).
Accordingly, it would have been obvious to one of ordinary skill in the art to generate a method for producing an RSV F protein trimer in a fed batch cell culture as taught by Baudoux at various temperatures known in the art, whereby the glucose is provided in a restricted manner to the cell culture by feeding glucose to the cell culture in response to rise of pH above a predetermined pH value as disclosed by Gagnon. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the fact that Baudoux discloses recombinant RSV F proteins can be produced at high titers in a stabilized trimer prefusion conformation in CHO cells that exhibit superior immunogenicity, and are particularly favorably employed as components of immunogenic compositions (e.g. vaccines) for protection against RSV infection and/or disease (paragraph [007]); and given the knowledge that Gagnon discloses “In the present work, we describe a method for very effective suppression of lactate accumulation during the growth phase of fed-batch cultures of CHO cells. The method is simple, scalable, requires no significant capital outlay at the largescale, and can result in dramatic increases in peak and sustained cell densities, cell viabilities, and overall bioreactor productivities. The method has been given the convenient acronym HIPDOG (HI-end pH-controlled Delivery Of Glucose)” (page 1329 first column first Para.) with temperatures at 37oC or 31oC (page 1329 first column); and given the knowledge as disclosed by Drapeau that it is considered routine in the art to determine at what temperature and concentration a particular cell should be cultured” (paragraph [0043]). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 5 and 16, with respect to lowering the temperature between day 3 and day 7, Baudoux in view of Gagnon and further in view of Drapeau, Gagnon discloses wherein the temperature is shifted to a lower temperature, wherein the lower temperature is 31oC, wherein the temperature is shifted to a lower temperature between day 3 and day 7 (page 1329 first column lines 11-48).
It would have been obvious for a skilled artisan to recognize when to shift the temperature. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the fact that Gagnon discloses wherein the temperature is shifted to a lower temperature between day 3 and day 7 (page 1329 lines 11-48) in order to achieve an optimal titer of the recombinant F protein in the prefusion trimer conformation. Additionally, in the absence of any unexpected results, the temperature selection and time/day for shifting to an optimal temperature defined in the instant claim therein only can be seen as an arbitrary selection which does not involve an inventive step in view of Gagnon and Drapeau. Moreover, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. According to section 2144.05 of the M.P.E.P., "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980) (instant claims 1 and 2). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 8, 10-11 and 14-15, Baudoux in view of Gagnon and further in view of Drapeau, Drapeau discloses the predetermined pH value corresponds to an increase of 0.01 to 0.10 above the pH set point of the culture (page 14, paragraphs 51-52; pages 31-34, claims 1, 8-11, 14-19, 25, 26, 29, 31).
It would have been obvious for a skilled artisan to provide glucose in a restricted manner in response to rise of pH above a predetermined pH value wherein the value corresponds to in increase of 0.01 to 0.10 above the pH set point of the culture as taught by Drapeau. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the fact that Drapeau discloses the predetermined pH value corresponds to an increase of 0.01 to 0.10 above the pH set point of the culture (page 14, paragraphs 51-52; pages 31-34, claims 1, 8-11, 14-19, 25, 26, 29, 31) in order to achieve an optimal titer of the recombinant F protein in the prefusion trimer conformation. Additionally, in the absence of any unexpected results, the temperature selection and time/day for shifting to an optimal temperature defined in the instant claim therein only can be seen as an arbitrary selection which does not involve an inventive step in view of Gagnon and Drapeau. Moreover, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. According to section 2144.05 of the M.P.E.P., "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980) (instant claims 1 and 2). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 38-40, Baudoux discloses RSV F protein subtypes A and B wherein the RSV F protein comprises mutations stabilizing the trimer in the prefusion conformation (page 2 paragraph [007] and page 21 paragraph [075]).
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Barry Chestnut whose telephone number is (571)270-3546. The examiner can normally be reached on M-Th 8:00 to 4:00.
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/BARRY A CHESTNUT/Primary Examiner, Art Unit 1672