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
The preliminary amendment filed June 10, 2024 has been received and entered.
Claims 8-9 have been amended.
Claims 10-20 have been added.
Claims 1-20 are pending and under consideration.
Priority
This application is a 371 of PCT/IN2022/050750 filed August 19, 2022, which claims the benefit of India Application No. 202141037886 filed August 20, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 5/22/2024 and 6/25/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1-4, 6-9, and 14-20 are objected to because of the following informalities:
Claims 1-3 recite “GOF glycoforms”, however, should contain a zero as in “G0F glycoforms”.
Claims 1-3 recite the term “glycoform”, which should be pluralized “glycoforms”.
Claims 1 and 3, step (c) recite “performing a temperature shift during cell culture…”, however, should read “performing a temperature shift during the cell culture process…”.
Claims 1 and 3 recite the term “culture media”, however, should recite “culture medium”.
Claim 2 (line 2) recites “comprises of about”, however, should recite “comprises about”.
Claim 4 recites “the difference between the first culture temperature and the second culture temperature of the cell culture”. The claim should be amended to read “of the cell culture medium”, or alternatively, delete the phrase “of the cell culture”.
Claim 4 recites the cell culture temperature shift ranges from 6.5°C to 2.5°C, however, the ranges should be listed as a shift in temperature of 2.5°C to 6.5°C.
Claim 6 recites “selected from about 30°C, about 32°C, about 34°C”, however, should read “selected from about 30°C, about 32°C, and about 34°C”.
Claims 7 and 14-18 recite “…wherein the galactose supplemented is about 6 g/L”, which is grammatically awkward. It is suggested the claims be amended to read “…wherein the amount of galactose that is supplemented is about 6 g/L”.
Claims 8-9 and 19-20 should read “anti-a4b7 integrin antibody”.
Appropriate correction is required.
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 1-20 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, step (e) recites “wherein the percentage of galactosylated glycoform in the antibody composition decreases with the decrease in the difference between the first culture temperature and the second culture temperature”. The phrase “decreases with the decrease in the difference…” is confusing as written. It is suggested that the claim be amended to read “wherein the percentage of galactosylated glycoforms in the antibody composition decreases between the first culture temperature and the second culture temperature”.
Additionally, the term “decreases with the decrease” in claim 1 step (e) is a relative term which renders the claim indefinite. The term “decrease” 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. Therefore, one of ordinary skill would not know the percentage of galactosylated glycoforms or the requisite decrease in temperature encompassed by the claim. For example, would it be infringing on the invention of claim 1 if the culture temperature decreases by 1°C and the percentage of galactosylated glycoforms decreases from 50% to 49%?
Lastly, claim 1 step (e) recites the percentage of galactosylated glycoforms in the antibody composition decreases. However, the preamble is drawn to an antibody composition comprising galactosylated and G0F glycoforms. As such it is unclear whether both galactosylated and G0F glycoforms decrease upon temperature shift, or just the galactosylated glycoforms as recited in the instant claims. Moreover, the limited instant specification provides no data regarding the glycan profile of the antibody (i.e., vedolizumab) prior to the temperature shift, thus providing no insight to the actual scope of the claims. However, the instant specification discloses that the glycan profile of the starting antibody (i.e., vedolizumab) was described in WO 2007/061679 (cited IDS 5/22/2024). Table 2 of the WIPO publication shows the glycosylation pattern of MLN02, now known as vedolizumab, wherein the MLN02 proteins produced by different CHO cell clones were mainly glycosylated with G0F oligosaccharide (agalactosylated, core fucosylated biantennary complex type), accounting for 58% to 76% of the total glycoforms observed. The G1F species (monogalactosylated core fucosylated biantennary complex type) accounted for only 15-30% of the total glycans, and the G2F (digalactosylated core fucosylated biantennary complex type) species accounted for less than 5% in all samples tested [pg. 38 and 43]. However, claim 2 recites the final antibody composition (i.e., vedolizumab) after the temperature shift comprises 41% to 47% galactosylated glycoforms and 47% to 52% G0F glycoforms. Therefore, how could the galactosylated glycoforms decrease to 41%-47% when the galactosylated glycoforms in the parent antibody composition comprise no more than 35% of the total glycans?
As such the claims are interpreted as a cell culture process resulting in an increased amount of galactosylated glycoforms and a decreased amount of G0F glycoforms in the antibody composition.
Claims 2, 5-8, 10, 12, 14, and 17-20 are included in the rejection as they ultimately depend from claim 1 and fail to clarify all the issues.
Claims 1 and 3, step (e) recite “the said recombinant antibody composition”, however, the claims do not recite a recombinant antibody composition in the previous steps. Accordingly, there is no antecedent basis for this limitation in the claims.
Claims 2, 8-9, and 19-20 recite “the antibody composition obtained…”. However, there is no basis for this limitation the preceding claims. It is recommended the claims be amended to recite “the recovered antibody composition…”.
Claim 3 is drawn to a cell culture process for producing a monoclonal antibody composition having target/predetermined levels of the reference product of the antibody variants.
It is unclear as to what “the reference product” or “the antibody variants” is referring, or what are “target/predetermined levels”.
The specification discloses the term "reference product" refers to a currently or previously marketed recombinant protein [pg. 5, lines 6-8]. The specification further discloses the term "target/predetermined levels" refers to the glycosylation levels of the “reference product” [pg. 5, lines 11-12]. Additionally, claim 3, step (e) refers to the antibody variants in the recovered recombinant antibody composition.
Therefore, the broadest reasonable interpretation (BRI) of the claims is a cell culture process for producing a monoclonal antibody composition beginning with an antibody with known glycosylation levels, further comprising decreasing the culture medium and recovering variants of the reference antibody comprising about 41 % to about 47% galactosylated glycoforms and about 47% to about 52% G0F glycoforms.
Claims 4, 9, 11, 13, and 15-16 are included in the rejection as they ultimately depend from claim 3 and fail to clarify all the issues.
Claim 3 recites the term “the second culture temperature is lower than the first culture temperature”. The term “lower” 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.
Claims 9 and 15-16 are included in the rejection as they ultimately depend from claim 3 and fail to clarify the issue.
Claims 8-9 and 19-20 recite “wherein the antibody composition obtained is an anti-a4b7 integrin antibody composition, vedolizumab”. However, it is unclear from the instant specification whether vedolizumab is the final product, or if the final product is a variant of vedolizumab.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gowtham et al. (WO 2020/252082; cited IDS 5/22/2024) (“Gowtham”).
The instant claims are drawn to a cell culture process for producing an antibody composition comprising galactosylated and G0F glycoforms, wherein the said process comprises providing mammalian cells expressing the said antibody, culturing the mammalian cells at a pH of 6.6 to 7.5, performing a temperature shift wherein the temperature is about 2.5°C to 6.5°C lower, supplementing the culture media with galactose, and recovering the antibody composition, wherein the percentage of galactosylated glycoforms in the antibody composition is decreased after the temperature decrease. The resulting antibody composition comprises about 41% to 47% galactosylated glycoforms and about 47% to 52% G0F glycoforms, wherein the antibody is an anti-a4b7 integrin known as vedolizumab.
Gowtham teaches cell culture methods for producing an anti-a4b7 antibody, such as vedolizumab, in mammalian host cells [pg. 2, lines 17-18](instant claims 8-9, 19-20), wherein the antibody composition has a decreased amount of G0F glycoforms in comparison to a control mammalian host cell expressing the antibody [pg. 8, lines 31-32] and an increased amount of G1F glycoforms and G2F glycoforms [pg. 9, lines 25-27; pg. 10, lines 17-18]. The overall process includes inoculation of cell culture medium with mammalian cells genetically modified to express the anti-a4b7 antibody, a growth phase, a production phase, and finally a harvesting stage whereby the recombinant antibody is collected. In between the various stages may be transition stages [pg. 73, lines 18-21](instant claims 1, 3 partial). Gowtham teaches the glycosylation profile can change when producing an anti-a4b7 antibody in cell culture, such as vedolizumab. The presence or absence of sialic acid or terminal galactose can alter the glycosylation profile, and can be controlled by modulating the amount of a sugar (e.g., galactose), in the culture medium. For example, the sugar in the supplement may be glucose, fucose or galactose [pg. 50, lines 20-21](instant claims 1, 3, 14-18 partial). Gowtham further teaches that a temperature shift may be employed during production [pg. 43, lines 8-10, lines 19-20].
The target level of G0F glycoforms in the final antibody composition is 40%-75% [pg. 58, lines 11-13], and the target levels of G1F and G2F glycoforms are 30%-40% and 2%-7%, respectively [pg. 59, lines 23-24; pg. 60, line 29](instant claims 2, 3 partial).
Gowtham teaches mammalian CHO cells are grown in culture medium with a pH between about 6.5 and 7.5 at 30°C to 40°C [pg. 75, lines 33-34; pg. 76, lines 1-2](instant claims 1, 3 partial). Typically the growth phase occurs at a higher temperature than a production phase. For example, a growth phase may occur at a first temperature from about 35°C to about 38°C, and a production phase may occur at a second temperature from about 30°C to about 34°C [pg. 76, lines 15-18](instant claims 1, 3 partial, 4, 6, 12-13).
Specifically, Gowtham teaches a cell culture procedure for producing vedolizumab comprising culturing the cells at 37°C for seven days and then shifting the temperature to 35°C or 33°C depending on study design [pg. 88, lines 1-4](instant claims 5, 10-11). Cultures were kept at a pH of 7.05 ± 0.15 or 6.85 ± 0.15 [pg. 87, Table 2]. The cells were fed a total of 6 g/L glucose, added in two bolus feeds [pg. 86, lines 30-33] (instant claims 7, 14-18).
The teachings of Gowtham differ from the present invention in that although a cell culture process for producing vedolizumab variants with a particular glycosylation profile comprising 40%-75% G0F glycoforms and 32%-47% of galactosylated glycoforms (i.e., G1F + G2F), wherein there is shift in culture temperature from 38°C to 30°C during the culturing process is disclosed, the culturing process is taught as using glucose (6 g/L) versus galactose (6 g/L). Given that Gowtham teaches that the culture medium can be supplemented with a sugar (glucose or galactose) during production to increase the overall yield of the antibody and a 6 g/L supplementation was better than 2 g/L, one of ordinary skill in the art would have more than a reasonable expectation of success in using 6 g/L galactose rather than 6 g/L glucose to produce a high yield of the vedolizumab glycan variants.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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