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 .
Response to Amendment
Applicant’s amendment filed 05/15/2026 is acknowledged. Claims 1 and 9 are amended, claim 8 is canceled, and claims 16-21 are new. Claims 1-7, 9-12, and 14-21 are under examination.
The amendment and remarks were filed with the incorrect serial number: 17/777954.
Withdrawn Rejections
Any previous rejections of claim 8 are hereby withdrawn in response to Applicant’s cancelation of the claim.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Double Patenting
The rejection of claims 1, 9, and 15 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 10-14 of U.S. Patent No. 10584169B2 is withdrawn.
The rejection of claims 1 and 9 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 10-14 of U.S. Patent No. 11613577B2 is withdrawn.
Applicant argues that U.S. Patent No. 10584169B2 and U.S. Patent No. 11613577B2 do not teach the formulation of the composition and therefore neither anticipates the instant claims.
This has been fully considered and is found to be persuasive. The instant claims are not directly anticipated by the patented claims because the pending instant claims require the pharmaceutical formulation components.
Maintained Rejections
Claim Rejections - 35 USC § 103
The rejection of claims 1-7, 9-12, and 14-15 under 35 U.S.C. 103 as being unpatentable over Wang et al. 2018 (WO2018137598-A1) in view of Boghaert et al. 2006 (WO2006031653-A2), Hilschmann et al. 1967, and Biddlecombie et al. 2019 (WO2019206987-A1) is maintained and extended to new claims 16-21. This is a modified rejection necessitated by Applicants’ amendments to the claims in the response filed on 05/15/2026, which remove the CRDs from claim 1 and move existing limitations into new dependent claims.
The amended instant claims are drawn to a composition formulation of an anti-CD73 antibody and a method of using the composition to treat cancer. The antibody comprises a heavy chain (VC) as set forth in SEQ ID NO: 9, comprising a heavy chain variable region (VH) as set forth in SEQ ID NO: 7, and a light chain (LC) as set forth in SEQ ID NO: 10, comprising a light chain variable region (VL) as set forth in SEQ ID NO: 8.
Wang teaches an anti-CD73 antibody and a method of treating cancer in a patient, where the cancer is bladder cancer (para [0003]-[0009], [0013]-[0019]). Wang teaches an anti-CD73 antibody with a VH with an identical sequence to instant SEQ ID NO: 7. The alignment data between Wang SEQ ID NO: 7 and instant SEQ ID NO: 7 is shown below.
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Wang teaches an anti-CD73 antibody with a light chain variable region (VL) with an identical sequence to instant SEQ ID NO: 8. The alignment data between Wang SEQ ID NO: 8 and instant SEQ ID NO: 8 is shown below.
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Wang does not teach the entirety of SEQ ID NOs: 9 and 10, only the VH and VL regions contained within them. Wang does not teach the composition of the anti-CD73 antibody formulation beyond the sequences.
Boghaert teaches an immunoglobulin heavy constant gamma 1 domain with identical sequence to SEQ ID NO: 9. The alignment data between the immunoglobulin heavy constant gamma 1 domain of Boghaert SEQ ID NO: 89 and instant SEQ ID NO: 9 is shown below.
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Hilschmann teaches a kappa constant domain with identical sequence to SEQ ID NO: 10. The alignment data between the kappa constant domain of Hilschmann and instant SEQ ID NO: 10 is shown below.
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Biddlecombie teaches an antibody formulation comprising 50mg/ml of a human anti-PD-L1 antibody, 25 mM histidine/histidine-HCl buffer, 275mM trehalose dehydrate (11.4% (w/v) trehalose dehydrate), 0.02% (w/v) polysorbate 80, and a pH of 6.0 (claims). Biddlecombie also discloses that the formulation is a liquid formulation, a frozen formulation, a lyophilized formulation, or a reconstituted formulation, including in water, and that the antibody formulation maintains stability at least three freeze/thaw cycles (see the section titled “Formulation” and claims 1, 3-7, 12-17, 20, & 25).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Wang in view of Boghaert and Hilschmann. One with ordinary skill in the art would be motivated to make and use the claimed invention because Wang teaches the variable domains of the anti-CD73 antibody treats cancer and is an IgG isotype (claim 5), but only specifies the variable domains and not the constant domains that are necessary to make an IgG isotype antibody. The constant domain is consistent in antibodies of the IgG isotype, using the gamma and kappa constant domains in their heavy and light chains, respectively. An ordinary artisan would have found it obvious to combine the variable domains of Wang with the gamma and kappa constant domains of Boghaert and Hilschmann to make an IgG isotype of the heavy and light chains of the anti-CD73 antibody, respectively, since the constant domains are consistent in IgG isotype antibodies. An ordinary artisan would have been motivated to do this in order to synthesize an antibody that treats cancer. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references.
Furthermore, it would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Wang, Boghaert, and Hilschmann in view of Biddlecombie. One with ordinary skill in the art would be motivated to make and use the claimed invention because Biddlecombie teaches that the disclosed antibody formulation improved stability of anti-PD1 antibody (page 1, lines 27-30; Fig 4). An ordinary artisan would have found it obvious to use the formulation as disclosed by Biddlecombie to improve the stability of the anti-CD73 antibody. An ordinary artisan would have been motivated to do this in order to make a stable antibody composition that treats cancer. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references.
In regards to claim 6 and 19, the prior art only differs from the claimed invention with respect to the concentration of trehalose dehydrate and antibody. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification states that effective embodiments of the claimed invention have a trehalose concentration ranging from 2-20% (para [0018]) and an antibody concentration ranging from 5-150mg/ml (para[0005]), which is evidence of its lack of criticality. The person of ordinary skill in the art would have been motivated, and found it obvious, to optimize the antibody formulation taught by Biddlecombie. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references.
Response to Arguments
Applicant argues that due to the difference in structures between the Biddlecombe anti-PD1 antibody and anti-CD73 antibody described in the claims: (1) the skilled artisan would not have looked to Biddlecombe anti-PD 1 antibody formulation for an anti-CD73 antibody; and (2) would not have had a reasonable expectation of success. Applicant argues that the Biddlecombe anti-PD 1 antibody and the anti-CD73 antibody target two different proteins, and would thus have different CDRs and different variable regions. Applicant argues that the rejection fails to provide a rationale as why a skilled artisan would specifically look to an anti-PD1 antibody, to stabilize an anti-CD73 antibody having a very different protein structure, and have a reasonable expectation of success. Applicant argues that the present application provides data illustrating the superiority of the formulation components described in the claims for use with the described antibodies. Applicant argues that development of a suitable formulation involves different considerations such as protein solubility and stability. Applicant argues that there are surprising benefits of the claimed formulation components for the antibody described in the claims. Applicant argues that, as an example, when different buffers were tested with the anti-CD73 antibody of the present disclosure, the phosphate buffer appeared to allow more fragmentation of the antibody to occur (see, e.g., Table 4) than other buffers. Applicant argues that it also led to more pronounced reduction of purity (Table 5). Applicant argues that these data also suggest that high (pH 7.0) and low (pH 4.5) pH conditions can also be detrimental to the purity of the protein (see also Table 6). (Paragraph [0012] of the present application.) Applicant argues that the application at paragraphs [0014]-[0015] summarize additional data pointing to the surprising benefits of the claimed formulation components for the antibody described in the claims. Applicant argues that, for example, the specification discloses that visible particles were detected in the formulation that contained mannitol, one of the most commonly used excipients for protein formulation, following freeze-thaw testing, even in the presence of PS80 (polysorbate 80), an excipient identified as important for stabilizing the protein during freeze-thaw cycles (see, for example, the specification at Tables 11 to 13). Applicant argues that the formulation with sucrose suffered the most fragmentation (see, for example, Table 17). Applicant argues that use of another excipient, arginine, also led to a relatively large (1%) decrease in protein purity (see, for example, Table 18). Applicant argues that another excipient, sorbitol, failed to sufficiently support protein stability during 10 cycles of freeze-thaw (see, for example, Table 23). Applicant argues that one of the candidate excipients, trehalose, was unexpectedly able to both keep the protein sufficiently stable through all these testing conditions and maintain antibody antigen-binding potency. Applicant argues that all of the claims provide for trehalose in combination with additional components, for use with a different antibody than described in Biddlecombe. Applicant provides no argument against the teaches of Wang, Boghaert, and Hilschmann and how these prior art references teach the limitations of the claims.
This has been fully considered, but is not found to be persuasive. Applicant argues that the antibodies have “very different protein structure,” yet an ordinary artisan would readily know that antibodies, which are also known as immunoglobulins, have a canonical Y-shaped structure constructed by two light chains and two heavy chains. The anti-PD 1 antibody and the anti-CD73 antibody both share this canonical structure. An ordinary artisan would readily understand that antibodies are by nature and purpose constructed with variable subcomponents that together form the canonical Y-shaped structure to target antigens. Said another way, although the antibodies have different sequences, they still share the classic antibody structure because they are immunoglobulins produced to target specific peptides. Therefore, Applicants argument that the anti-PD 1 antibody and the anti-CD73 antibody have “very different protein structure” simply because they “target two different proteins and would thus have different CDRs and different variable region” is not found to be persuasive. In regards to the “surprising” and “unexpected” results Applicant argues are demonstrated in the specification, these alleged inventions amount to mere validation of the antibody formulation taught by Biddlecombe. As Biddlecombe already teaches the antibody formulation, it is neither “surprising” or “unexpected” that the formulation would be efficacious and could be optimized. The “superiority of the formulation components” amount to routine optimization that any ordinary artisan would find obvious. For example, Applicant’s argument that trehalose was unexpectedly able to both keep the protein sufficiently stable through all testing conditions and maintain antibody antigen-binding potency is obvious and not unexpected because Biddlecombie already teaches that the antibody formulation containing trehalose improved stability. Likewise the “surprising benefits” that Applicant argues of using a histidine, polysorbate 80, and a pH of 5.8-6.2 (instead of mannitol, sucrose, arginine, and sorbitol), amounts to the mere optimization of a known antibody formulation. As such, this argument is not found to be persuasive.
New Rejections
Claims 1, 8-9, and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 10-14 of U.S. Patent No. 10584169B2 in view of Biddlecombie et al. 2019 (WO2019206987-A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims recite a composition of an anti-CD73 antibody and a method of using the composition to treat cancer, comprising SEQ ID NOs: 7-8.
The patented claims recite a method of treating cancer by administering an anti-CD73 antibody, comprising SEQ ID NOs: 7-8.
Instant SEQ NOs: 7-8 have identical sequences to patented SEQ ID NOs: 7-8. However, the co-pending claims do not explicitly teach the pharmaceutical formulation beyond the anti-CD73 antibody.
Biddlecombie teaches an antibody formulation comprising 50mg/ml of a human anti-PD-L1 antibody, 25 mM histidine/histidine-HCl buffer, 275mM trehalose dehydrate (11.4% (w/v) trehalose dehydrate), 0.02% (w/v) polysorbate 80, and a pH of 6.0 (claims). Biddlecombie also discloses that the formulation is a liquid formulation, a frozen formulation, a lyophilized formulation, or a reconstituted formulation, including in water, and that the antibody formulation maintains stability at least three freeze/thaw cycles (see the section titled “Formulation” and claims 1, 3-7, 12-17, 20, & 25).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention by formulating the patented antibody in the pharmaceutical composition of Biddlecombie. One with ordinary skill in the art would be motivated to make and use the claimed invention because Biddlecombie teaches that the disclosed antibody formulation improved stability of anti-PD1 antibody (page 1, lines 27-30; Fig 4). An ordinary artisan would have found it obvious to use the formulation as disclosed by Biddlecombie to improve the stability of the anti-CD73 antibody. An ordinary artisan would have been motivated to do this in order to make a stable antibody composition that treats cancer. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Further, regarding the specific concentrations for all of the components of the composition, these are art recognized variables and therefore, one would engage in routine optimization to obtain the desired result of a stable formulation for the composition, thus arriving at these specific concentrations as claimed. See MPEP 2144.05 (II). The prior art only differs from the claimed invention with respect to the concentration of trehalose dehydrate and antibody. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention because an ordinary artisan would have found it obvious to optimize the formulation through routine experimentation. An ordinary artisan would have been motivated to optimize the formulation to make the most stable and effective composition. MPEP 2144 sets forth Applicant’s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification states that effective embodiments of the claimed invention have a trehalose concentration ranging from 2-20% (para [0018]) and an antibody concentration ranging from 5-150mg/ml (para[0005]), which is evidence of its lack of criticality. The person of ordinary skill in the art would have been motivated, and found it obvious, to optimize the antibody formulation taught by Biddlecombie. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references.
Claims 1 and 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 10-14 of U.S. Patent No. 11613577B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims recite a composition of an anti-CD73 antibody, comprising SEQ ID NOs: 7-8.
The patented claims recite a composition of an anti-CD73 antibody, comprising SEQ ID NOs: 7-8.
Instant SEQ NOs: 7-8 have identical sequences to patented SEQ ID NOs: 7-8. However, the co-pending claims do not explicitly teach the pharmaceutical formulation beyond the anti-CD73 antibody.
Biddlecombie teaches an antibody formulation comprising 50mg/ml of a human anti-PD-L1 antibody, 25 mM histidine/histidine-HCl buffer, 275mM trehalose dehydrate (11.4% (w/v) trehalose dehydrate), 0.02% (w/v) polysorbate 80, and a pH of 6.0 (claims). Biddlecombie also discloses that the formulation is a liquid formulation, a frozen formulation, a lyophilized formulation, or a reconstituted formulation, including in water, and that the antibody formulation maintains stability at least three freeze/thaw cycles (see the section titled “Formulation” and claims 1, 3-7, 12-17, 20, & 25).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention by formulating the patented antibody in the pharmaceutical composition of Biddlecombie. One with ordinary skill in the art would be motivated to make and use the claimed invention because Biddlecombie teaches that the disclosed antibody formulation improved stability of anti-PD1 antibody (page 1, lines 27-30; Fig 4). An ordinary artisan would have found it obvious to use the formulation as disclosed by Biddlecombie to improve the stability of the anti-CD73 antibody. An ordinary artisan would have been motivated to do this in order to make a stable antibody composition that treats cancer. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Further, regarding the specific concentrations for all of the components of the composition, these are art recognized variables and therefore, one would engage in routine optimization to obtain the desired result of a stable formulation for the composition, thus arriving at these specific concentrations as claimed. See MPEP 2144.05 (II). The prior art only differs from the claimed invention with respect to the concentration of trehalose dehydrate and antibody. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention because an ordinary artisan would have found it obvious to optimize the formulation through routine experimentation. An ordinary artisan would have been motivated to optimize the formulation to make the most stable and effective composition. MPEP 2144 sets forth Applicant’s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification states that effective embodiments of the claimed invention have a trehalose concentration ranging from 2-20% (para [0018]) and an antibody concentration ranging from 5-150mg/ml (para[0005]), which is evidence of its lack of criticality. The person of ordinary skill in the art would have been motivated, and found it obvious, to optimize the antibody formulation taught by Biddlecombie. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references.
Conclusion
No claims are allowed.
Advisory Information
This action is Non-Final.
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/JOSEPH D. CESARE/ Examiner, Art Unit 1675 /JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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