DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment to the claims, filed September 3, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are pending in the application.
Election/Restrictions
Applicant’s election without traverse of species 2), increasing the concentration of each of zinc and manganese and, optionally, decreasing the concentration of each of iron and copper to increase N-glycan maturity in the expressed glycoprotein, wherein the carbohydrate portion of the expressed glycoprotein has a G0, G1 or G2 structure and wherein the concentrations of zinc, manganese, iron and copper are adjusted to:
(a) iron - from 0 µM to 25 µM;
(b) copper - from 0 µM to 0.1 µM;
(c) zinc - from 20 µM to more than 50 µM; and
(d) manganese - from 0.01 µM to more than 3 µM
in the reply filed on September 3, 2026 is acknowledged.
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are being examined on the merits with claim 1 being examined only to the extent the claim reads on the elected subject matter.
Priority
This application is filed under 35 U.S.C. 120 as a continuation of U.S. non-provisional application no. 17/006,463, filed August 28, 2020, now abandoned, which is filed under 35 U.S.C. 120 as a continuation of U.S. non-provisional application no. 15/236,348, filed August 12, 2016, now abandoned, which is filed under 35 U.S.C. 120 as a continuation of international application PCT/EP2015/053804, filed on February 24, 2015, which claims foreign priority under 35 U.S.C. 119(a)-(d) to European application no. 14157030.9, filed February 27, 2014.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 2, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Claim Objections
Claims 1, 2, 12, 13, and 26 are objected to because of the following informalities:
Claim 1 is objected to in the recitation of “wherein the adjustment is,” in line 5 and in order to conform to Markush claim language (MPEP 2117), it is suggested that the noted phrase be amended to recite “wherein the adjustment is selected from the group consisting of.”
Claims 1, 2, 12, 13, and 26 are objected to in the inconsistent recitation of “the recombinant glycoprotein,” “the produced glycoprotein,” and “the glycoprotein” to refer to the same glycoprotein. In the interest of improving claim form, it is suggested that only a single term or phrase be used to refer to the glycoprotein, e.g., amending claims 1, 2, and 13 to replace “the produced glycoprotein” or “the glycoprotein” with “the recombinant glycoprotein.”
Claim Rejections - Improper Markush Grouping
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are rejected on the basis that claim 1 contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117. Where a Markush grouping describes part of a combination or process, the members following “selected from the group consisting of” (or a similar introductory phrase) must be substitutable, one for the other, with the expectation that the same intended result would be achieved. See MPEP § 803.02.II.
The Markush grouping of claim 1 (claims 2, 12, 13, 15, 16, 18, and 26-28 dependent therefrom) recites a list of alternative steps for adjusting concentrations of iron, copper, zinc, and manganese to achieve different results, i.e., adjusting concentrations of iron, copper, zinc, and manganese to increase biomass generation, increase N-glycan maturity in the produced glycoprotein, or increase production of immature non-fucosylated glycoproteins. The Markush grouping of claim 1 is improper because the alternatives defined by the Markush grouping are not substitutable, one for the other, with the expectation that the same intended result would be achieved.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 (claims 2, 12, 13, 15, 16, 18, and 26-28 dependent therefrom) is confusing and inconsistent in the recitation of “adjusting the concentrations of each of iron, copper…wherein the adjustment is…optionally, decreasing the concentration of each of iron and copper…and wherein the concentrations of…iron and copper are adjusted to.” One of skill in the art would recognize that “adjusting the concentrations of each of iron, copper” in lines 2-3 is a required step while “optionally, decreasing the concentration of each of iron and copper” in lines 12-13 is an optional step. In this case, it is unclear as to whether claim 1 requires adjusting/decreasing the concentrations of iron and copper or, alternatively, adjusting/decreasing the concentrations of iron and copper is merely optional.
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.
Claims 1, 12, 15, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kenerson, R. (US 2005/0287666 A1; cited on the IDS filed June 2, 2025; hereafter “Kenerson”).
Claims 1, 12, 15, 16, and 18 are drawn to a method for production of a recombinant glycoprotein under fermentation culture conditions in a mammalian cell, the method comprising adjusting the concentrations of each of iron, copper, zinc and manganese in the culture medium during the culture to affect biomass generation and/or N-glycan maturity in the produced glycoprotein, wherein the adjustment is,
- increasing the concentration of each of zinc and manganese and, optionally, decreasing the concentration of each of iron and copper to increase N-glycan maturity in the expressed glycoprotein, wherein the carbohydrate portion of the expressed glycoprotein has a G0, G1 or G2 structure and wherein the concentrations of zinc, manganese, iron and copper are adjusted to:
(a) iron - from 0 µM to 25 µM;
(b) copper - from 0 µM to 0.1 µM;
(c) zinc - from 20 µM to more than 50 µM; and
(d) manganese - from 0.01 µM to more than 3 µM,
wherein a decrease in the bioavailable concentration of any or all of iron, copper, zinc and manganese in the culture medium is achieved by seeding the cells into a fresh medium containing a reduced concentration of any or all of iron, copper, zinc and manganese compared to the medium of the immediately preceding culture phase.
Given a broadest reasonable interpretation, the recitation of “to affect biomass generation and/or N-glycan maturity in the produced glycoprotein” in claim 1 is interpreted as an intended purpose of adjusting the concentrations of zinc and manganese and optionally iron and copper in the culture medium. See MPEP 2111.02.II regarding preamble statements reciting purpose or intended use.
In view of the inconsistencies in the recitation of “adjusting the concentrations of each of iron, copper…wherein the adjustment is…optionally, decreasing the concentration of each of iron and copper…and wherein the concentrations of…iron and copper are adjusted to” in claim 1 and given a broadest reasonable interpretation, the noted phrase is interpreted as meaning the adjusting/decreasing of the concentrations of iron and copper is optional and the recitation of “to increase N-glycan maturity in the expressed glycoprotein, wherein the carbohydrate portion of the expressed glycoprotein has a G0, G1 or G2 structure” is in reference to and is an intended purpose of the optional adjusting/decreasing of the concentrations of iron and copper.
Kenerson is related to an improved cell culture media, media supplements, and methods of culturing cells (Abstract).
Regarding instant claim 1, Kenerson teaches the present invention provides a culture medium or medium supplement comprising zinc and manganese (paragraph [0065]).
Regarding the concentration of zinc, Kenerson teaches zinc may be present at >10-5 M, i.e., >10 µM (paragraph [0046]). Kenerson teaches preferred working ranges and favored concentrations in Tables 1, 2, and 3 including zinc chloride at a working range of 0.184 µM to 18.4 µM (paragraph [0160] and Table 1). According to MPEP 2144.05.I, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Given that the recited range of “zinc - from 20 µM to more than 50 µM” does not overlap with but is close to Kenerson’s teaching of zinc being present at >10 µM and zinc chloride at a working range of 0.184 µM to 18.4 µM, a prima facie case of obviousness exists.
Regarding the concentration of manganese, Kenerson teaches preferred working ranges and favored concentrations in Tables 1, 2, and 3 including manganese sulfate H2O at a working range of 8.99E-9 µM to 0.00899 µM (paragraph [0160] and Table 1). According to MPEP 2144.05.I, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Given that the recited range of “manganese - from 0.01 µM to more than 3 µM” does not overlap with but is close to Kenerson’s teaching of manganese being present at a working range of 8.99E-9 µM to 0.00899 µM, a prima facie case of obviousness exists.
Kenerson teaches the present invention provides a medium or a supplement that when added to basal medium improves cell culture, noting that improved culture may be exhibited by more rapid cell growth, decreased doubling time, higher achievable density of cells, higher production or yield of biomolecule (paragraph [0060]).
Kenerson teaches the present invention may be used in any culture process, especially biomolecule-producing cells, e.g., mammalian cells, and that bioproduction may include glycoprotein production (paragraph [0054]).
Kenerson teaches the target cell is grown to a desired cell density in a cell culture medium optimized for growth of the cell and once the desired density is reached, the medium is exchanged for a medium optimized for the transfection process, which does not support the growth of the cells but is merely used for the purpose of introducing nucleic acids into the cells (paragraph [0031]). Kenerson teaches that after a period of time sufficient for uptake of the macro molecule, removing the transfection medium and washing the remnants of the transfection medium from the cells and then re-suspending the transfected cells in a growth medium (paragraph [0031]).
Given that Kenerson teaches the transfection medium does not support cell growth, it would have been obvious to one of ordinary skill in the art before the effective filing date to use a transfection medium that does not comprise zinc and manganese and to remove the transfection medium and re-suspend transfected cells in a growth medium with zinc and manganese concentrations within the recited ranges of from 20 µM to more than 50 µM and from 0.01 µM to more than 3 µM, respectively.
Regarding instant claim 12, given a broadest reasonable interpretation, the phrase “the recombinant glycoprotein is…endogenous to the mammalian cell” is interpreted as meaning the recombinant glycoprotein is produced inside of the mammalian cell. Kenerson teaches the present invention may be used in any culture process, especially biomolecule-producing cells, e.g., mammalian cells, and that bioproduction may include glycoprotein production (paragraph [0053]). Given that glycoproteins are produced inside a mammalian cell, the glycoprotein produced by a mammalian cell according to Kenerson is considered to be endogenous to the mammalian cell.
Regarding instant claim 15, as stated above, Kenerson teaches that after a period of time sufficient for uptake of the macro molecule, removing the transfection medium and washing the remnants of the transfection medium from the cells and then re-suspending the transfected cells in a growth medium (paragraph [0031]). One of ordinary skill in the art would have recognized that a growth medium is intended for a growth and/or production culture phases.
Regarding instant claim 16, Kenerson teaches the supplement is added to a basal medium to improve cell culture (paragraph [0060]; Example 1 beginning at paragraph [0165]).
Regarding instant claim 18, given a broadest reasonable interpretation, the recitation of “first to increase biomass generation and then to increase N-glycan maturity in the produced N-glycoproteins, or to increase production of immature non-fucosylated glycoproteins” is interpreted as an intended purpose of adjusting the concentrations of each of iron, copper, zinc and manganese in the culture medium and does not require any additional step(s) to be performed beyond the method step(s) recited in claim 1. See MPEP 2111.02.II regarding preamble statements reciting purpose or intended use.
Therefore, the invention of claims 1, 12, 15, 16, and 18 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 2, 13, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kenerson in view of Wang et al. (ACS Chem. Biol. 7:110-122, 2012; cited on the attached Form PTO-892; hereafter “Wang”).
Claim 2 is drawn to the method of claim 1 wherein the expressed glycoprotein is a mature N-glycosylated glycoprotein, a mature non-fucosylated glycoprotein or an immature non-fucosylated glycoprotein.
Claim 13 is drawn to the method according to claim 12 wherein the glycoprotein is an antibody.
Claim 26 is drawn to the method of claim 1, wherein the recombinant glycoprotein is a structural glycoprotein, a hormone, an antibody or an enzyme.
Claim 27 is drawn to the method of claim 13, wherein the antibody is a therapeutic antibody or diagnostic antibody.
Claim 28 is drawn to the method of claim 27, wherein the therapeutic antibody or diagnostic antibody is a chimeric antibody, a humanized antibody or a human antibody.
The relevant teachings of Kenerson as applied to claims 1, 12, 15, 16, and 18 are set forth above.
While Kenerson teaches bioproduction may include glycoprotein production (paragraph [0054]), and further teaches bioproduction may include antibody production (paragraph [0054]) and the improved culture may be exhibited by higher production or yield of biomolecule such as an antibody or other proteins of therapeutic interest (paragraph [0060]), Kenerson does not teach the glycoprotein is a mature N-glycosylated glycoprotein (claim 2), the glycoprotein is an antibody (claims 13 and 26), the glycoprotein is a therapeutic antibody (claim 27), and the glycoprotein is a therapeutic human antibody (claim 28).
Wang reviews emerging technologies for making glycan-defined glycoproteins (title).
Regarding instant claim 2, Wang teaches the biosynthesis of mammalian glycoproteins involves N-glycosylation (p. 111, column 1, middle) and Figure 2 of Wang (p. 112) shows N-glycan biosynthetic pathways including the processing and branching in a mammalian host leading to mature glycoproteins (Figure 2b).
In view of the combined teachings of Kenerson and Wang, it would have been obvious to one of ordinary skill in the art before the effective filing date for the glycoprotein of Kenerson to be a mature N-glycosylated glycoprotein. One would have been motivated and would have expected success for the glycoprotein of Kenerson to be a mature N-glycosylated glycoprotein because Wang taught the biosynthesis of mammalian glycoproteins involves N-glycosylation Wang shows N-glycan biosynthetic pathways including the processing and branching in a mammalian host leading to mature glycoproteins.
Regarding instant claims 13 and 26-28, Wang teaches compelling evidence has shown that appropriate glycosylation is important for biological activities of therapeutic glycoproteins (p. 110, column 2, top). Wang teaches recombinant therapeutic glycoproteins currently used in clinical treatment include monoclonal antibodies (p. 111, column 1, middle). Wang teaches human IgG-Fc expressed from CHO cells (p. 117, column 1, bottom).
In view of the combined teachings of Kenerson and Wang, it would have been obvious to one of ordinary skill in the art before the effective filing date for the glycoprotein of Kenerson to be a therapeutic antibody including a therapeutic human antibody. One would have been motivated and would have expected success for the glycoprotein of Kenerson to be a therapeutic antibody because Kenerson taught bioproduction may include glycoprotein and antibody production, Kenerson taught the improved culture may be exhibited by higher production or yield of biomolecule such as an antibody or other proteins of therapeutic interest, and Wang taught therapeutic glycoproteins include monoclonal antibodies and taught mammalian cell-based expression of human IgG-Fc, which is a therapeutic human antibody.
Therefore, the invention of claims 2, 13, and 26-28 would have been obvious to one of ordinary skill in the art before the effective filing date.
Citation of Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2009/126564 A1 (cited on the attached Form PTO-892) discloses inhibiting sialidase expression in a mammalian cell culture for glycoprotein production by including zinc at a concentration of between 0.005 mM and 50 mM (p. 3, paragraph [0017]).
Conclusion
Status of the claims:
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are pending.
Claims 1, 2, 12, 13, 15, 16, 18, and 26-28 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached on Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
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