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
Election/Restrictions
Applicant’s election without traverse of Group II claims 16-27 and species: histidine buffer, sucrose, polysorbate 80 in the reply filed 07/25/2025 is acknowledged.
Claims 28 and 35 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 07/25/2025.
Claims 16, 18-27, and new claims 37-41 are now under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
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 16, 18-27, and new claims 37-41 are rejected under 35 U.S.C. 103 as being unpatentable over Loffredo et al. (US 2019/0382490 A1, in IDS filed 09/07/2022), in view of Carroll et al. (US 20090110681 A1, in instant PTO-892).
Loffredo et al. teaches sequences for the anti-CTLA-4 antibody, with the anti-CTLA-4 antibody with enhanced ADCC activity comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences of SEQ ID NOs: 3-8, respectively. In another embodiment, the anti-CTLA-4 antibody with enhanced ADCC activity comprises the VH and VL sequences of SEQ ID NOs: 9 and 10, respectively. In a further embodiment, the anti-CTLA-4 antibody with enhanced ADCC activity comprises the HC sequence of SEQ ID NO: 11, and the LC sequence of SEQ ID NO: 13, see paragraph 0005. These sequences are a match to the following instant sequences:
Reference’s SEQ ID NO: 11 is a 100% match to instant SEQ ID NO: 1
Reference’s SEQ ID NO: 13 is a 100% match to instant SEQ ID NO: 2
Reference’s SEQ ID NO: 3 is a 100% match to instant SEQ ID NO: 12
Reference’s SEQ ID NO: 4 is a 100% match to instant SEQ ID NO: 13
Reference’s SEQ ID NO: 5 is a 100% match to instant SEQ ID NO: 14
Reference’s SEQ ID NO: 6 is a 100% match to instant SEQ ID NO: 15
Reference’s SEQ ID NO: 7 is a 100% match to instant SEQ ID NO: 16
Reference’s SEQ ID NO: 8 is a 100% match to instant SEQ ID NO: 17
Reference’s SEQ ID NO: 9 is a 100% match to instant SEQ ID NO: 18
Reference’s SEQ ID NO: 10 is a 100% match to instant SEQ ID NO: 19
Loffredo et al. teach a nonfucosylated ipilimumab antibody, comprising a heavy and light chain sequences SEQ ID NOs: 11 and 13, which are 100% matches to instant SEQ ID NOs: 1 and 2, see reference’s claims 5 and 16. The ipilimumab antibody is specific for CTLA-4 markers on cells. The antibody taught by Loffredo also teaches that “modification of antibody glycosylation can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Antibodies with reduced or eliminated fucosylation, which exhibit enhanced ADCC, are particularly useful in the methods of the present invention. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of this disclosure to thereby produce an antibody with altered glycosylation. For example, the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (α-(1,6) fucosyltransferase”, see paragraph 0079.
However, Loffredo et al. does not teach the formulation for the instant antibody. Carroll et al. remedies this deficiency.
Carroll et al. teaches formulations for antibody compositions comprising a chelating agent, see Abstract. Carroll et al. teaches antibody concentrations of 1 mg/mL to about 200 mg/mL, 0.01 mg/mL to about 1.0 mg/mL of EDTA, 1 mM to about 100 mM of a histidine buffer, and 0.01 to about 2 mg/mL of polysorbate 80, see reference’s claims 15-19. Carroll et al. also teaches an embodiment wherein the sucrose concentration is “10 mg/ml to about 200 mg/ml of sucrose”, see paragraph 0211. Carroll et al. teaches that the buffer “is used to maintain an acceptable pH level (which can affect antibody stability) in the liquid pharmaceutical composition… In one embodiment, the liquid pharmaceutical composition is buffered to maintain a pH of about 5.5. In another embodiment, the liquid pharmaceutical composition is buffered to maintain a pH of about 6.0”, see paragraph 0140.
Carroll et al. also teaches that the formulation comprises tonicity agents that include “saccharides that are suitable for use as a tonicity agent in the present invention, include, but are not limited to, saccharides selected from the group consisting of fructose, glucose, mannose, sorbose, xylose, lactose, maltose, sucrose, dextran, pullulan, dextrin, cyclodextrins, soluble starch, hydroxyethyl starch, water-soluble glucans, and mixtures thereof”, see paragraph 0143. Carroll et al. teaches that the formulation comprises the “suitable salts of EDTA include dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate, trisodium edetate, and potassium edetate; and a suitable salt of deferoxamine (DEF) is deferoxamine mesylate (DFM)”, see paragraph 0129.
Carroll et al. teaches that the formulation comprises excipients or carrier, which are “used herein refers to an inert substance, which is commonly used as a diluent, vehicle, preservative, binder or stabilizing agent for drugs. As used herein, the term “diluent” refers to a pharmaceutically acceptable (safe and non-toxic for administration to a human) solvent and is useful for the preparation of the compositions herein. Exemplary diluents include, but are not limited to, sterile water and bacteriostatic water for injection (BWFI)”, see paragraph 0116.
It would be obvious at the time of the instant invention to use the antibody taught by Loffredo et al., which is a monoclonal antibody that teaches the instantly claimed sequences and cell conditions to produce the claimed fucosylation of the antibody, with the formulation taught by Carroll et al. which teaches compositions that are known to provide stability for antibodies in formulation. One would be motivated to combine the antibody with the formulation with the expectation of preserving the stability of the antibody in solution, and produce the claimed glycoforms when placed in the same conditions.
Therefore, claims 16, 18-27, and new claims 37-41 are rejected as obvious over Loffredo et al. and Carroll et al.
Response to Arguments
Applicant's arguments filed 01/07/2026 have been fully considered but they are not persuasive.
Applicant argues “Loffredo fails to teach or suggest the claimed antibody formulation” and “Carroll fails to remedy the deficiencies of Loffredo, because Carroll doesn’t teach or suggest anti-CTLA-4 antibody formulations at all”. This is not found persuasive.
Loffredo et al. was relied upon to teach the sequences of the instant antibody, which shows that before the time of the invention and without knowledge of the invention, the structure and identity of the instantly claimed anti-CTLA-4 antibody was known. Carroll et al. teaches formulations for antibody compositions, and uses an example containing an anti-MSF antibody in a liquid formulation. When combined, the teachings of Loffredo et al. and Carroll et al. arrive at the instant antibody and formulation as the limitations for both are explicitly taught in the prior art. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that combining the references would not have been known at the time of filing, but this is unpersuasive. Given that both the antibody and formulation are both found in the art, combining the two would have been obvious because one of ordinary skill in the art could perform routine experimentation to combine the teachings and arrive at the instant result. It is well known that the optimization of a pharmaceutical formulation for an antibody (e.g., modification of pH or excipient concentration) is considered routine and conventional within the art, and the argument that modification of the formulation renders the instant formulation distinct from the formulation of the prior art is not persuasive for nonobviousness. It would have been obvious to the ordinary artisan to modify the composition to improve certain characteristics like antibody stability and decrease viscosity because it was already known that such changes could be advantageous when preparing pharmaceutical compositions for antibodies. One of ordinary skill in the art would argue that the stability observed after modification and optimization of the composition was expected, especially in the view of the art recognized need to develop stable antibody formulations and to modify the formulation to provide the best stability for a specific antibody through routine optimization. Modifying the composition to reach this endpoint is a part of routine optimization.
Additionally, there is sufficient teaching and guidance in the prior art at the time of filing for one of ordinary skill in the art to experimentally arrive at the claimed values from the ranges taught by the prior art. The limitations recited in the instant claims are predictable because the art teaches the rationale behind each addition to the formulation, which a skilled artisan can adjust depending upon the structure and identity of a particular antibody. The prior art teaches ranges for each of the additions to the formulations, which encapsulates the fact that the art recognizes that there needs to be adjustments made to formulations to adapt to the unique requirements of specific antibodies based on amino acid compositions. The prior art disclosures themselves speak to the fact that formulations are not static and depend on multiple factors to achieve the conditions a specific protein requires to be stable in an aqueous formulation. As such, certain endpoints could be routine experimented for and determined based on the existing guidance within the prior art.
The instant claims are drawn to a composition and as such, the combination of references from the prior art address each of the components of the composition and render it obvious. The prior art describes broader ranges for the components of the formulation, and a skilled artisan can experiment to obtain certain values dependent upon their end target.
Applicant argues “there is no motivation for a person skilled in the art to combine Loffredo with Carroll in a manner to arrive at the claimed formulation, and no reasonable expectation of success.” This is not found persuasive.
One of ordinary skill in the art would be motivated to combine the references because it would be routine to perform routine experimentation when creating antibody formulations. Certain characteristics, such as pH or turbidity, can be experimentally tested for and selected from within a broader range set forth in the art. As such, one of ordinary skill would have a reasonable expectation of success in arriving at the instant invention.
Therefore, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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