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
The Amendment filed 12/8/2025 in response to Office Action of 8/7/2025, is acknowledged and has been entered. Claims 20-21, 23, 25-29, and 34-58 are now pending. Claim 20 is amended. Claims 23, 25, 40-43, and 48-58 remain withdrawn. Claims 20-21, 26-29, 34-39, and 44-47 are currently being examined.
Maintained Rejection
(Arguments and Amendment Addressed)
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.
Claim(s) 20-21, 26-29, 34, 37, and 38-39 remain rejected under 35 U.S.C. 103 as being unpatentable over Abdiche et al (US20160159905 A1, published: 06/09/2016), in view of Gomez-Navarro et al (US20090074787 A1, published 3/19/2009), Shenoy et al (WO2018211517 A1, filed 06/20/2017), and Tomar et al (Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development, mAbs, vol 8, issue 2, Published: 2/2016).
Abdiche teaches a pharmaceutical composition, comprising: an anti-PD1 antibody, a histidine buffer, sugar component, polysorbate 80, and EDTA. [0007, 0013, 0213, 0275] Abidche teaches the construct, mAB7 or PF-0681591, wherein the construct is provided in: 20 mM histidine buffer, 85 mg/mL sucrose, 0.2 mg/ml polysorbate 80, and 0.05 disodium EDTA, and the pH is 5.5. [0348] Abdiche teaches that that the sugar component of the pharmaceutical composition may be sucrose or trehalose as a stabilizing agent. [0213, 0275] Abdiche teaches that mAB7 is an anti-PD-1 antagonist antibody. [0115] Abdiche teaches that the anti-PD-1 antibody may be a human or humanized antibody. Abdiche teaches that the antibody is an IgG4 antibody, an IgG4 S228P antibody. [0012-0013] Abdiche teaches that the composition may be lyophilized. [0221] Abidche teaches that the anti-PD-1 antibody comprises a heavy chain variable region (VH) comprising a VH complementarity determining region (CDR1), VH CDR2, and a VH CDR3 of the VH sequence shown in SEQ ID NO: 4, which matches 100% to the instantly claimed SEQ ID NO: 2, and/or a light chain variable region (VL) comprising VL CDR1, a VL CDR2, and a VL CDR3 of the VL sequence shown in SEQ ID NO: 8, which matches 100% to the instantly claimed SEQ ID NO: 3. Abidche teaches that the VH CDR1 comprises the amino acid sequence shown in SEQ ID NO: 13, which matches 100% to the instantly claimed SEQ ID NO: 4, the VH CDR2 comprises the amino acid sequence shown in SEQ ID NO: 17, which matches 100% to the instantly claimed SEQ ID NO: 5, the VH CDR3 comprises the amino acid sequence shown in SEQ ID NO: 23, which matches 100% to the instantly claimed SEQ ID NO: 6, the VL CDR1 comprises the amino acid sequence shown in SEQ ID NO: 10, which matches 100% to the instantly claimed SEQ ID NO: 7, the VL CDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, which matches 100% to the instantly claimed SEQ ID NO: 8, the VL CDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, which matches 100% to the instantly claimed SEQ ID NO: 9. (claim 12) Abidche teaches that the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 29, which matches 100% to the instantly claimed SEQ ID NO: 10, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 39, which matches 100% to the instantly claimed SEQ ID NO: 11. [0010] Abidche teaches that modifications may be made in the framework region or constant region in order to increase the half-life of the anti-PD-1 antibody, and teaches that these modifications may be glycosylation with different sugars. [0157] teaches that glycosylation of antibodies is typically either N-linked or O-linked, and that N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. [0158] Abidche’s heavy chain amino acid sequence, SEQ ID NO: 29, which matches 100% to the instantly claimed SEQ ID NO: 10, has an asparagine at amino acid position 294.
However, Abdiche did not teach: (1) the exact concentration of the anti-PD1 antibody, (2) the exact concentration of trehalose, (3) the viscosity of the composition, or (4) that the pH is exactly 5.0 +/- 0.1.
Gomez-Navarro teaches a pharmaceutical composition: comprising: an antibody (anti-CTLA-4), a histidine buffer, sugar component (Trehalose) polysorbate 80, and EDTA. Gomez-Navarro teaches that the following composition components: an antibody, 20 mM histidine buffer, 84 mg/ml trehalose dihydrate, 0.2 mg/ml polysorbate 80, and 0.1 mg/ml disodium EDTA dihydrate. [0225]
Shenoy teaches that a challenge with administering protein agent-based therapeutics, such as antibodies, include high viscosity. [0002-0003] Shenoy teaches that the concentration of a protein agent in high concentration and low viscosity formulation may be 150 mg/ml. [0010] Shenoy teaches that preparation have a viscosity of about 20 centipoise or lower. Shenoy teaches that preparing this liquid formulation includes: (1) protein agent, (2) histidine buffer, (3) a viscosity-reducing agents, such as trehalose dehydrate, polysorbate 80, and/or EDTA. [0191-0192] Shenoy teaches that low-viscosity protein agent formulations allow for greater flexibility in formulation development and can be used to deliver an effective amount of a protein agent. [0240] Shenoy teaches that the use of sugars, such as sucrose or trehalose, increase the stability of a protein agent. [0230] Shenoy teaches that the pH of the antibody formulations may range and can be adjusted based on necessity, for example to maximize stability and solubility of a polypeptide in a particular protein agent formulation. [0030, 0031, 0179, 0253]
Tomar teaches that highly concentrated monoclonal antibodies drug solutions have the added benefit of longer intervals between the injections, and these benefits can lead to reduced healthcare costs by minimizing hospital or clinic visits, as well as increasing patient compliance and adherence. Tomar teaches that the benefits of having highly concentrated monoclonal antibodies is that they can demonstrate high viscosities, which can lead to difficulties in developing drug products suitable for certain formulations. Tomar teaches that high viscosity of a concentrated antibody increase injection time and pain at the site of injection, difficulties during bioprocesses of the drug substance, and also pose difficulties during the manufacturing phase. (Introduction) Tomar teaches strategies of lowering viscosity in antibody formulation, including changing the formulation components, such as the buffer, pH and excipients. [pg.6-7]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add 150 mg/ml of the anti-PD-1 antibody in the method of Abdiche. One would have been motivated to because: (1) Abidche teaches a pharmaceutical composition that comprises, an anti-PD-1 antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA, (2) Gomez-Navarro teaches a pharmaceutical composition with an antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA, and (3) Shenoy teaches that the protein agent in their formulation may be 150 mg/ml. One of ordinary skill in the art would have a reasonable expectation of success because: (1) Gomez-Navarro successfully demonstrates making a pharmaceutical composition of an antibody, with the exact instantly claimed concentrations of the histidine buffer, polysorbate 80 and EDTA. Given the recognized need to make pharmaceutical compositions of anti-PD1 antibody, and given the known methods and concentrations of the agents and excipients listed in the claims, one of skill in the art could have pursued using 150 mg/ml of the anti-PD-1 antibody in the method of Abdiche, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose for the 85 mg/ml of sucrose in the method of Abidche. One would have been motivated to, because (1) Abidche and Gomez-Navarro both teach a pharmaceutical composition that comprises, an anti-PD-1 antibody, a histidine buffer, a sugar component, polysorbate 80, and EDTA, (2) Abidche teaches the antibody comprises a sugar component for stability, and states that this component may be sucrose or trehalose, and (3) Shenoy teaches that the use of sugars, including trehalose or sucrose, in protein agent-based therapeutics increases the stability of a protein agent. One of ordinary skill in the art would have a reasonable expectation of success, because Gomez-Navarro successfully demonstrates making a pharmaceutical composition of an antibody with the exact instantly claimed concentration of trehalose: 84 mg/ml. One of skill in the art could have substituted one known sugar component concentration for another, and the results of a pharmaceutical composition comprising the instantly claimed components and substitutions, would have been predicable.
It is noted that claim 21 requires that the viscosity of the composition is between 10-18 cP or 15 cP at 20°C. This limitation would have been obvious to those of ordinary skill in the art because: (1) Abidche teaches a pharmaceutical composition that comprises, an anti-PD-1 antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA, (2) Gomez-Navarro teaches a pharmaceutical composition with an antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA, and (3) Shenoy teaches that preparing a protein-agent based therapeutic, such as antibody, should have a low viscosity, <20 cP, and that this includes preparing a liquid formulation with an antibody, histidine buffer and viscosity lowering agents, such as trehalose dehydrate, polysorbate 80, and/or EDA. One of ordinary skill in the art would have a reasonable expectation of success because: (1) Gomez-Navarro successfully demonstrates making a pharmaceutically composition of an antibody, with the exact instantly claimed concentrations of the histidine buffer, polysorbate 80 and EDTA, (2) Shenoy teaches and demonstrates how to lower viscosity in order to allow for greater flexibility in developing the antibody formulation in order to deliver an effective amount of a protein agents, (3) Shenoy teaches that agents that can lower viscosity include trehalose, polysorbate 80 and/or EDTA, and (4) Tomar teaches that high viscosity has several disadvantages and that lowering the viscosity by altering formulation components, will allow for several benefits for both drug manufacturing and the patient. Given the recognized need to make high concentration and low viscosity pharmaceutical compositions of antibodies, and given the known methods of lowering viscosity and the agents that can lower viscosity, one of skill in the art could have prepared a pharmaceutical composition with the concentrations in the prior art and confirmed the viscosity of the composition to be about 10-20 cP at 20°C as claimed, with a reasonable expectation of success.
It is noted that claim 22 requires that the pH of the composition is 5.0 +/- 0.1. This limitation would have been obvious to those of ordinary skill in the art because Abidche teaches a pharmaceutical composition that comprises, an anti-PD-1 antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA and teaches that the pH may be 5.5. One of ordinary skill in the art would have a reasonable expectation of success because: (1) Gomez-Navarro successfully demonstrates making a pharmaceutical composition of an antibody, with the exact instantly claimed concentrations of the histidine buffer, polysorbate 80 and EDTA, and (2) Shenoy teaches that the pH of the antibody formulations may range and can be adjusted based on necessity, for example to maximize stability and solubility of a polypeptide in a particular protein agent formulation. Given the recognized need to make pharmaceutical compositions of anti-PD1 antibody, and given the known methods of adjusting pH based on factors to maximize stability and solubility, one of skill in the art could have pursued making pH of the pharmaceutical composition 5.0 +/- 0.1, with a reasonable expectation of success.
Claim(s) 44-47 remain rejected under 35 U.S.C. 103 as being unpatentable over Abdiche et al (US20160159905 A1, Published: 06/09/2016), Gomez-Navarro et al (US20090074787 A1, published 3/19/2009), Shenoy et al (WO2018211517 A1, Filed 06/20/2017), and Tomar et al (Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development, mAbs, vol 8, issue 2, Published: 2/2016) (combined references) as applied to claims 20-21, 26-29, 34, 37, and 38 above, and further in view of Chumsae et al (Journal of Chromatography B, 850 (2007) 285–294) and Thakkar et al (Excipients Differentially Influence the Conformational Stability and Pretransition Dynamics of Two IgG1 Monoclonal Antibodies, Journal of Pharmaceutical Sciences, Volume 101, Issue 9, September 2012, Pages 3062-3077).
The combined references teachings are stated above. However, they do not explicitly mention that the composition does not comprise an antioxidant (methionine), or arginine.
Chumsae teaches recombinant monoclonal antibodies possess a lot of features that can cause instability of molecules through many degradation pathways, including oxidation. Chumsae teaches that methionine is the most susceptible amino acid for oxidation in proteins. [pg 293, col 1]
Thakkar teaches that arginine was found to be a potent destabilizer in monoclonal antibodies. Thakkar teaches arginine that the destabilizing effect of arginine could be due to intermolecular β-structure-rich oligomer formation and/or promotion of its dissociation, and that the destabilization of these intermediates’ structures, stabilize partially altered structures of the monoclonal antibody and forms larger aggregates. [pg 3074, col 2]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed exclude a methionine or arginine in the method of Abdiche. One would have been motivated, and have a reasonable expectation of success because: (1) Chumsae teaches that oxidation can cause instability of monoclonal antibodies, and that methionine is the most susceptible amino acid for oxidation, (2) Thakkar teaches that arginine was found to be a potent destabilizer in monoclonal antibody formulations, and (3) Abidche and Gomez-Navarro both explicitly teach and successfully demonstrate a pharmaceutical composition that comprises, an antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA. Given the recognized need to make pharmaceutical compositions of anti-PD1 antibody, and given the known methods and negative implications of adding methionine and/or arginine, one of skill in the art could have pursued excluding arginine and methionine, with a reasonable expectation of success.
Claim(s) 35-36 remain rejected under 35 U.S.C. 103 as being unpatentable over Abdiche et al (US20160159905 A1, Published: 06/09/2016), Gomez-Navarro et al (US20090074787 A1, published 3/19/2009), Shenoy et al (WO2018211517 A1, Filed 06/20/2017), and Tomar et al (Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development, mAbs, vol 8, issue 2, Published: 2/2016), as applied to claims 20-21, 26-29, 34, 37, and 38 above (combined references), and further in view of Reusch et al (Fc glycans of therapeutic antibodies as critical quality attributes, Glycobiology, Vol 25, Dec. 2015, pages 1325-1334), and Li et al (Pharamcological significance of glycosylation in therapeutic proteins, Current Opinion in Biotechnology, Vol 20, December 2009, pages 678-684)
The combined references teachings are stated above. However, they do not explicitly teach glycosylation at Asn294 comprising G0F and G1F as the main glycan species, and that the glycosylation further comprises as minor glycan species truncated and/or afcusoylated complex-type biantennary structures, a high mannose Man5 structure,
Reusch et al teaches that N-glycosylation is one of the most important post-translational modifications and has a remarkable heterogeneity of protein glycoforms. Reusch teaches that the use of mammalian expression systems result in complex type biantennary oligosaccharides in the Fc portions, and that the most common glycostructures commonly found in the Fc portion of the therapeutic antibody are G0F and G1F. Reusch teaches that for therapeutic antibodies, the typical abundance for G0F and G1F is 35.5% and 42.4%, respectively. Reusch also teaches that these antibodies may also comprise minor glycan species or high-mannose structure. [Table 1, pg 1325 column 2]
Li teaches that glycosylation is the process by which oligosaccharide side chains are covalently attached to either side chain of asparagine (N-linked). Li teaches that N-linked glycosylation is the most common and that this is important for signaling, recognition and interaction events within and between cells and proteins. Li teaches the process of glycosylation and teaches that the preferred site for N-glycsylation contains the three amino acid sequence, Asn-Xaa-Ser/Thr, where the second position can be any amino acid except Pro. [pg 679, col 1]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to glycosylate Asn294 comprising G0F and G1F as the main glycan species and further comprises minor glycan species truncated and/or high mannose structures. One would have been motivated to because: (1) Abidche teaches that there may be modifications in the anti-PD-1 antibody in order to increase half-life, including N-linked glycosylation, (2) Reusch and Li teach that n-glycosylation is an important post-translational modification, (2) Reusch teaches the major glycan species of therapeutic antibodies that include G0F and G1F, as well as minor glycan species or high mannose structures, and (3) Abidche teaches SEQ ID NO: 29 (which matches instantly claimed SEQ ID NO: 10), which has an asparagine at position 294. One would have had a reasonable expectation of success because Li teaches that the preferred site for N-clygosylation contains the three amino acids, Asn-Xaa-Ser/Thr and (2) at the site 294 in the heavy chain of the amino acid for Abdiche’s anti-PD-1 antibody, (SEQ ID NO: 29), the amino acids are: Asn-Ser-Thr. Given the recognized need in the art for N-glycosylation of therapeutic antibodies, and given the known methods as discussed by prior art, one of skill in the art could have pursued glycosylation at Asn294 comprising G0F and G1F as the main glycan species and minor glycan truncated species as claimed, with a reasonable expectation of success.
Response to Arguments
Applicant reiterates arguments and argues the following:
That Abidche formulation is the closest prior art disclosure related to the present invention in claim 20, and that although Abidche taught that trehalose can be used as a sugar, it taught that other disaccharides, monosaccharides other sugars and carbohydrates can be used, and did not teach in what ways trehalose would be better than sucrose. Applicant argues that Gomez-Navarro taught 84 mg/ml trehalose dihydrate for a low concentration CTLA4 antibody formulation and that a POSA would not have the motivation to substitute 85 mg/ml sucrose in the Abidche formulation with 84 mg/mg trehalose a high concentration and a low mAb7 formulation and have a reasonable expectation of success. Applicant argues that Shenoy mentioned both sucrose and trehalose as potential agents among a 10-page long list of alternative viscosity-reducing agents. Applicant argues that Tomar teaches that sugars increase viscosity more than monosaccharaides and teaches away from using trehalose and taught away from pH lower than 5.2.
Applicant argues that that the claimed formulation has unexpected results. Applicant provides data from the Applicant’s lab notebook in the formulation compared to the formulation described in Abidche. Applicant argues that using 84 mg/ml trehalose in Formula 7 and pH at 5.0 +/- reduced viscosity of the PD-1 antibody mAb7 formulation described in Abdiche.
Applicant’s arguments have been considered but are not persuasive. The claims are drawn to a pharmaceutical composition comprising or consisting of:
150 mg/ml of an anti-PD-1 antibody
20 mM of a histidine buffer
84 mg/ml trehalose
0.2 mg/ml PS80
0.045 or about 0.05 mg/ml EDTA
wherein said pharmaceutical composition is pH 5.0 +/- .0.1
Abidche (the primary reference) teaches a pharmaceutical composition comprising: (1) the instantly claimed anti-PD-1 antibody, (2) 20 mM of histidine buffer, (3) 85 mg/ml sucrose, (4) 0.2 mg/ml PS80, and (5) 0.05 mg/ml EDTA. Although Abidche does not teach the use of trehalose, Abidche does teach the use of trehalose as a sugar component for the purpose of stabilization. [see para. 0213, 0275]
The Examiner relied on the combination of the secondary references to remedy the deficiencies of Abdiche.
Gomez-Navarro teaches a pharmaceutical composition with an antibody, a histidine buffer, trehalose, polysorbate 80, and EDTA. Gomez-Navarro successfully demonstrates making a pharmaceutical composition of an antibody, with the exact instantly claimed concentrations of the histidine buffer, polysorbate 80. Furthermore, Gomez-Navarro teaches and successfully demonstrates an antibody composition comprising 84 mg/ml trehalose dihydrate. The purpose of Shenoy is to acknowledges that a challenge with administering protein agent-based therapeutics, such as antibodies, include high viscosity, and further teaches that the concentration of a protein agent in high concentration and low viscosity formulation may be 150 mg/ml, and further emphasizes that that the use of sugars, such as sucrose or trehalose, increase the stability of a protein agent. [see para. 234] As stated in previous office action, although Tomar does not state exactly what to change, this reference was not the only reference the Examiner relied on: Shenoy teaches that preparing a protein-agent based therapeutic, such as antibody, should have a low viscosity, <20 cP, and that this includes preparing a liquid formulation with an antibody, histidine buffer and viscosity lowering agents, such as trehalose dehydrate, polysorbate 80, and/or EDTA, Shenoy teaches that agents that can lower viscosity include trehalose, polysorbate 80 and/or EDTA, and Tomar teaches that high viscosity has several disadvantages and that lowering the viscosity by altering formulation components, will allow for several benefits for both drug manufacturing and the patient. The Examiner also did not use the reference of Tomar to demonstrate pH of the composition as noted in the 103 rejection above.
The Applicant states that the composition comprising the exact concentrations is unexpected results. However, this property of having reduced viscosity is expected based on the disclosure of the prior art. As noted above, the references teach the issue with high viscosity is known in the art, and potential ways to remedy this, including adding agents, such as trehalose, at the concentration, is known and taught by the prior art as noted above. Thus, it would have been expected to reduce viscosity of agents, including adding trehalose at a concentration of 84 mg/ml in high concentration antibodies, over the disclosures of the prior art.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/SARAH A ALSOMAIRY/ Examiner, Art Unit 1646
/Zachariah Lucas/ Supervisory Patent Examiner, Art Unit 1600