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. Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are pending.
Priority
3. Acknowledgement is made of applicants’ claimed domestic priority to U.S. Provisional Application No. 63/157902, filed on 03/08/2021.
Information Disclosure Statement
4. The IDSs filed on 04/09/2024 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Drawings
5. The Drawings filed on 09/01/2023 are acknowledged and accepted by the examiner.
Claim Rejections - 35 USC § 112(a)
6. 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.
A. Written Description
7. Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are 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.
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.
Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 41 and 43 are drawn to a method for reducing a high mannose glycan (HMG) content of a protein expressed during a mammalian cell culture process, comprising: (1) establishing a mammalian cell culture expressing the protein; and (2) contacting the cell culture with Guanosine 5’-monophosphate (GMP) or an agent that increases GMP de novo synthesis; wherein the HMG is Man 5. The structure of the agent that increases GMP de novo synthesis is unlimited.
Claims 32, 34, 39, 42, and 44 are drawn to a cell culture medium for reducing HMG content of a protein expressed during a mammalian cell culture process, comprising GMP or an agent that increases GMP de novo synthesis. The structure of the agent that increases GMP de novo synthesis is unlimited.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of agents that increase GMP de novo synthesis as encompassed by the claims (i.e. guanosine monophosphate, inosine monophosphate, xanthine monophosphate, guanosine diphosphate, guanosine triphosphate, guanosine 3’,5’-cyclic monophosphate, guanine, IMP dehydrogenase, and GMP synthase). Other than the above disclosed species there is no other drawings or structural formulas disclosed of any other agents that increase GMP de novo synthesis as encompassed by the claims.
Ledesma-Amaro et al. (Process Biochemistry, 2013; examiner cited) teach that both IMP and GMP are metabolic products of the purine biosynthetic pathway, and the de novo purine pathway leads to the conversion of PRPP and glutamine into IMP through 10 different enzymatic reactions making IMP the central metabolite in the purine pathway [see p. 1264, column 2]. Ledesma-Amaro et al. further teach that the purine biosynthetic network is connected to many other important metabolic pathways [see p. 1264, column 2, bottom].
To this end, given the many mechanisms of GMP synthesis as evidenced by Ledesma-Amaro et al., there is no further prior art or disclosed teach of the of infinite number of agents as encompassed by the claims that can increase GMP de novo synthesis. The breadth of the claims encompass any agent, such nucleoside monophosphates, small molecules, inhibitors, enzymes, etc. that can be added to a cell culture to result in increased GMP synthesis. As such, in the instant case, there is no disclosed correlation between and structure and function to adequately describe the genus of agents as encompassed by the claims that result in an increase in GMP de novo synthesis. Accordingly, one of skill in the art would not accept the disclosure of guanosine monophosphate, inosine monophosphate, xanthine monophosphate, guanosine diphosphate, guanosine triphosphate, guanosine 3’,5’-cyclic monophosphate, guanine, IMP dehydrogenase, and GMP synthase as being representative of all agents as encompassed by the claims that result in an increase in GMP de novo synthesis. Therefore, the specification, taken with the pre-existing knowledge in the art of GMP de novo synthesis, fails to satisfy the written description requirement of 35 U.S.C. 112(a).
B. Scope of Enablement
8. Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a cell culture medium comprising guanosine monophosphate, inosine monophosphate, xanthine monophosphate, guanosine diphosphate, guanosine triphosphate, guanosine 3’,5’-cyclic monophosphate, guanine, IMP dehydrogenase, and GMP synthase for increasing GMP de novo synthesis in a mammalian cell culture process, does not reasonably provide enablement for all agents that increase GMP de novo synthesis as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these 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: Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 41 and 43 are drawn to a method for reducing a high mannose glycan (HMG) content of a protein expressed during a mammalian cell culture process, comprising: (1) establishing a mammalian cell culture expressing the protein; and (2) contacting the cell culture with Guanosine 5’-monophosphate (GMP) or an agent that increases GMP de novo synthesis; wherein the HMG is Man 5. The structure of the agent that increases GMP de novo synthesis is unlimited.
Claims 32, 34, 39, 42, and 44 are drawn to a cell culture medium for reducing HMG content of a protein expressed during a mammalian cell culture process, comprising GMP or an agent that increases GMP de novo synthesis. The structure of the agent that increases GMP de novo synthesis 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: The scope of the claimed agents that increase GMP de novo synthesis is unlimited. The breadth of the claims encompass any agent, such nucleoside monophosphates, small molecules, inhibitors, enzymes, etc. that can be added to a cell culture to result in increased GMP synthesis.
Ledesma-Amaro et al. (Process Biochemistry, 2013; examiner cited) teach that both IMP and GMP are metabolic products of the purine biosynthetic pathway, and the de novo purine pathway leads to the conversion of PRPP and glutamine into IMP through 10 different enzymatic reactions making IMP the central metabolite in the purine pathway [see p. 1264, column 2]. Ledesma-Amaro et al. further teach that the purine biosynthetic network is connected to many other important metabolic pathways [see p. 1264, column 2, bottom].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of agents that increase GMP de novo synthesis, i.e. guanosine monophosphate, inosine monophosphate, xanthine monophosphate, guanosine diphosphate, guanosine triphosphate, guanosine 3’,5’-cyclic monophosphate, guanine, IMP dehydrogenase, and GMP synthase. Other than these working examples, the specification fails to disclose any other working examples of agents that increase GMP de novo synthesis.
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).
Claim Rejections - 35 USC § 101
9. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
10. Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial excpetion without significantly more. Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 41 and 43 recite a method of reducing a high mannose glycan content of a protein expressed during a mammalian cell culture process, comprising: (1) establishing a mammalian cell culture expressing the protein, and (2) contacting the cell culture with GMP or an agent that increases GMP de novo synthesis, wherein the HMG is Man 5. Claims 32, 34, 39, 42, and 44 recite a cell culture medium for reducing HMG content of a protein expressed during a mammalian cell culture process, comprising GMP or an agent that increases GMP de novo synthesis, wherein the GMP or the agent that increases GMP de novo synthesis is at a final concentration sufficient to reduce the HMG content of the protein by at least 1% compared to the protein expressed in an essentially same cell culture medium except that the essentially same cell culture medium does not include GMP or the agent that increases GMP de novo synthesis. This judicial exception is not integrated into a practical application because the method is not markedly different from a natural process. Furthermore, the cell culture medium is not markedly different from a natural product, such as a mammalian cell or mammalian organism. GMP is a natural compound found in mammalian cells and its presence in mammalian cells naturally increases GMP synthesis in turn decreasing the high mannose glycan content of glycoproteins. Ledesma-Amaro et al. (Process Biochemistry, 2013; examiner cited) teach that both IMP and GMP are metabolic products of the purine biosynthetic pathway, and the de novo purine pathway leads to the conversion of PRPP and glutamine into IMP through 10 different enzymatic reactions making IMP the central metabolite in the purine pathway [see p. 1264, column 2]. Ledesma-Amaro et al. further teach that the purine biosynthetic network is connected to many other important metabolic pathways [see p. 1264, column 2, bottom]. Furthermore, in eukaryotic cells genes for both AMP and GMP synthesis are negatively regulated by extracellular purines and particularly PRPP amidotransferase is inhibited by AMP, GMP and IMP [see p. 1265]. Accordingly, the methods reducing high mannose glycan read on the natural metabolic regulatory process in eukaryotic cells. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because limiting the method to different agents and concentrations limit the agents to natural products already found and regulated by purine biosynthesis pathways found in eukaryotic cells. Accordingly, the methods and cell culture medium of claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are not patent eligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
11. 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.
12. Claim(s) 1, 4-5, 17, 20, 24, 27-29, 32, 39, 41, 42, and 43-44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Collins et al. (US Patent Application Publication 2012/0277165 A1; cited on IDS filed on 04/09/2024).
13. Claims 1, 4-5, 17, 20, 24, 27-29, 41 and 43 are drawn to a method of reducing a high mannose glycan content of a protein expressed during a mammalian cell culture process, comprising: (1) establishing a mammalian cell culture expressing the protein, and (2) contacting the cell culture with GMP or an agent that increases GMP de novo synthesis, wherein the HMG is Man 5.
Claims 32, 34, 39, 42, and 44 are drawn to a cell culture medium for reducing HMG content of a protein expressed during a mammalian cell culture process, comprising GMP or an agent that increases GMP de novo synthesis, wherein the GMP or the agent that increases GMP de novo synthesis is at a final concentration sufficient to reduce the HMG content of the protein by at least 1% compared to the protein expressed in an essentially same cell culture medium except that the essentially same cell culture medium does not include GMP or the agent that increases GMP de novo synthesis.
14. With respect to claim 1, Collins et al. teach a method of reducing high mannose glycan content of protein expressed during a mammalian cell culture process comprising: establishing a mammalian cell culture expressing the protein, and contacting the cell culture with guanosine 5’-monophosphate or another inhibitor to decrease levels of GDP-mannose and subsequently high mannose glycans [see Abstract; paragraphs 0004, 0009-0010, 0079]. Although Collins et al. does not explicitly teach that the HMG is Man 5, given that GDP-mannose is the basis for high mannose glycosylation of proteins, it is the examiner’s position that absent evidence otherwise, a reducing in GDP-mannose levels would inherently result in reducing Man 5. Since the Office does not have the facilities for examining and comparing applicants’ method with the method of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed method and the method of the prior art (i.e., that the method of the prior art does not possess the same material structural and functional characteristics of the claimed method). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 4, Collins et al. teach the method wherein step 2 comprises contacting the cell culture with GMP [see Abstract; paragraphs 0004, 0009-0010, 0079, 0122, 0133].
With respect to claim 5, Collins et al. teach the method wherein the agent that increases GMP de novo synthesis is guanosine diphosphate (GDP) [see paragraphs 0079 and 0133]. Although Collins et al. does not teach that the agent increases GMP de novo synthesis, given that Collins teaches an identical agent in identical methods, it is the examiner’s position that the increase GMP de novo synthesis is an inherent feature of the GDP agent taught by Collins. Since the Office does not have the facilities for examining and comparing applicants’ method with the method of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed GDP and the GDP of the prior art (i.e., that the GDP of the prior art does not possess the same material structural and functional characteristics of the claimed GDP). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 17, Collins et al. teach the method wherein the cell culture is maintained by perfusion and teach selecting a time at which cell cultures are started or stopped, and selecting a time at which cell culture parameters are changed (interpreted as partial or entire period) [see paragraphs 0607-0608].
With respect to claim 20, Collins et al. teach the method wherein the cell culture is maintained by fed batch and teach selecting a time at which cell cultures are started or stopped, and selecting a time at which cell culture parameters are changed (interpreted as partial or entire period) [see paragraphs 0607-0608].
With respect to claims 24 and 27-29, Collins et al. teach the method wherein the high mannose glycan content of the protein is reduced 10%, 20%, and 30% [see paragraphs 0008-0009].
With respect to claim 32, Collins et al. teach a cell culture medium for reducing HMG content of a protein expressed during a mammalian cell culture process, comprising GMP, wherein the GMP concentration is sufficient to reduce HMG content of the protein by at least 1% [see Abstract; paragraphs 0004, 0008-0010, 0079].
With respect to claim 39, Collins et al. teach wherein the agent that increases GMP de novo synthesis is guanosine diphosphate (GDP) [see paragraphs 0079 and 0133]. Although Collins et al. does not teach that the agent increases GMP de novo synthesis, given that Collins teaches an identical agent in identical methods, it is the examiner’s position that the increase GMP de novo synthesis is an inherent feature of the GDP agent taught by Collins. Since the Office does not have the facilities for examining and comparing applicants’ culture medium with the culture medium of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed GDP and the GDP of the prior art (i.e., that the GDP of the prior art does not possess the same material structural and functional characteristics of the claimed GDP). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 41, Collins et al. teach the method wherein the mammalian cell culture is a CHO cell culture medium [see paragraph 0053].
With respect to claim 42, Collins et al. teach the mammalian cell culture is a CHO cell culture medium [see paragraph 0053].
With respect to claim 43, Collins et al. teach the method wherein the protein is a monoclonal antibody [see paragraph 0066].
With respect to claim 44, Collins et al. teach the cell culture medium wherein the protein is a monoclonal antibody [see paragraph 0066].
Claim Rejections - 35 USC § 103
15. 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.
16. Claim(s) 9, 14, 23, and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al. (US Patent Application Publication 2012/0277165 A1; cited on IDS filed on 04/09/2024).
17. The relevant teachings of Collins et al. as applied to claims 1, 4-5, 17, 20, 24, 27-29, 32, 39, 41, 42, and 43-44 are set forth above.
With respect to claims 9, 14, 23, and 34, Collins et al. teach a method and cell cultures of reducing high mannose glycan content of protein expressed during a mammalian cell culture process comprising: establishing a mammalian cell culture expressing the protein, and contacting the cell culture with guanosine 5’-monophosphate or another inhibitor to decrease levels of GDP-mannose and subsequently high mannose glycans [see Abstract; paragraphs 0004, 0009-0010, 0079].
Although Collins et al. does not explicitly teach the methods and cell culture medium of claims 9 and 34 wherein the GMP is at a final concentration of 1-25 mM; the method of claim 14, wherein the GMP is added to the cell culture between 3 and 15 days after the cell culture is established; and the method of claim 23, wherein the cell culture is maintained by combinations of perfusion and fed batch for a partial or entire period of the cell culture, Collins et al. does teach that production parameters than can be selected include addition or removal of media including when and how often media is harvested; increasing or decreasing speed at which cell cultures are agitated; increasing or decreasing temperature; adding or removing media such that cell culture density is adjusted; selecting a time at which cell cultures are started or stopped; and selecting a time at which cell culture parameters are changed and such parameters can be selected for any of the batch, fed-batch, perfusion and continuous culture conditions [see paragraph 0608]. As such, before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to optimize these parameters using the teachings of Collins et al., and one of ordinary skill in the art would desire to do so in order to maximize the condition desired by Collins et al., either decreased high mannose or increased high mannose. 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.
Conclusion
18. Status of the claims:
Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are pending.
Claims 1, 4-5, 9, 14, 17, 20, 23-24, 27-29, 32, 34, 39, and 41-44 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656