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 .
Claims Status
Claims 1-13, 15-36, 39-43, 45-48, 52-55, 58-61 and new claims 62-70 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 17, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Withdrawn Objections/Rejections
Any objection or rejection of record pertaining to cancelled claims 14, 37-38, and 44 is rendered moot by applicant’s cancellation of said claim.
The objection of claims 1 and 6-7 are withdrawn in view of applicant’s amendment.
The rejections of claims 9-10, 19-22, 29-34, 39-42, and 58-61 under 35 U.S.C. 112(b) as being indefinite are withdrawn in view of applicant’s amendment.
The rejection of claims on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of copending Application No. 18/246,467 is withdrawn. The claims of ‘467 have been amended, and they no longer read on the claimed composition.
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 1-13, 15-36, 39-43, 45-48, 52-55, 58-61 and new claims 62-70 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180044419, published February 15, 2018 (“Rosengren”; U.S. Patent Application reference 105 in IDS from 2/6/2024) in view of US 20190330363, published October 31, 2019 (“Jansson”; instant IDS) and US 20210155913, with an effective filing date of July 25, 2018 (“Park”; U.S. Patent Application reference 116 in IDS from 9/5/23).
The instant claims are directed to a pharmaceutical composition comprising 75-200 mg/ml anti-PD-1 antibody, 0.0009-0.050 mg/ml PH20 variant, buffer at pH 5.0-6.4, 3-10% w/v nonreducing disaccharide, and 0.005-0.10% non-ionic surfactant.
Rosengren teaches pharmaceutical compositions comprised of an immune checkpoint inhibitor and an anti-hyaluronan agent [0468]; the immune checkpoint inhibitor can be an anti-PD-1 antibody [0022] and the hyaluron-degrading enzyme can be the hyaluronidase PH20 (HuPH20) [0012], as in instant claim 1. Rosengren teaches the anti-PD1 antibody pembrolizumab for use in the combination therapy of immune checkpoint inhibitor and hyaluronidase [0377], as in instant claim 47. The antibody concentration in the formulation can be between 0.5 mg/ml and 250 mg/ml [0623], which completely overlaps with the ranges and doses in instant claims 1, 13, 15-18, 23-34, and 58-61. Rosengren teaches that the concentration of the hyaluronidase is 10-12,800 U/ml [0612], which overlaps with the ranges and dosages of instant claims 1, 19-34, 58-61, and new claim 70 (300-17,667 U/ml, when 0.0009-0.050 mg/ml is converted to U/ml; where 2000 U/ml of PH20 variant fragment is about 0.012 mg/ml and 4000 U/ml of PH20 variant fragment is about 0.024 mg/ml, see pg 21 of specification).
Further, Rosengren teaches that a pharmaceutical composition for the checkpoint inhibitor can include the excipient sucrose [0589], as in instant claims 1, 6-7, 23-34, 58-61, and new claim 63, and the non-ionic surfactant polysorbate 80 at 0.001-0.1% ([0589],[0616]), as in instant claims 1, 8-10, 23-34, 60-61 and new claim 62. Rosengren also teaches that the pharmaceutical composition can be comprised of an oxygen scavenger, such as methionine [0615], as in instant claims 11-12, 23-34, and 58-61.
The composition of Rosengren can be provided as a liquid or a lyophilized formulation [0573]; the lyophilized form can be reconstituted just prior to use by an appropriate buffer [0575], as in claims 35-36.
Rosengren teaches that the anti-PD-1 antibody pembrolizumab is comprised a heavy chain variable region (HCVR) of SEQ ID NO: 68 and a light chain variable region (LCVR) of SEQ ID NO: 70 [0377], which are identical to HCVR of SEQ ID NO: 9 and LCVR of SEQ ID NO: 4 of instant claims 45 and 48. Rosengren heavy chain of SEQ ID NO: 64 and light chain SEQ ID NO: 66 [0377] are identical to instant heavy chain of SEQ ID NO: 10 and instant light chain of SEQ ID NO: 5 of claim 46 and new claims 64-69. Rosengren HCVR and LCVR are comprised of the same HCDR1-3 of SEQ ID NO: 6, 7, and 8 and LCDR1-3 of SEQ ID NO: 1, 2, and 3 of instant claim 1.
Rosengren does not teach a formulation comprising the claimed ranges of sucrose or methionine nor do they teach a PH20 variant SEQ ID NO: 21 with modifications consisting of: amino acid residue substitutions T341 S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L3520, L353A, L354I, D355K, N356E, E359D and I361T in SEQ ID NO: 21; an N-terminus deletion of amino acid residues 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, or 1-42 of SEQ ID NO: 21; and a C-terminus deletion of amino acid residues 466-509, 467-509, 468-509, 469-509, 470-509, 471-509, 472-509, 473-509, 474-509, 475-509, 476-509, 477-509, 478-509, 479-509, 480-509, 481-509, 482-509, 483-509, 484-509, 485-509, 486-509, 487-509, 488-509, 489-509, 490-509, and 491-509, wherein the numbering is by reference to SEQ ID NO: 21.
Jansson teaches that the amount of pharmaceutically acceptable carriers in the pharmaceutical composition comprised of an antibody and a hyaluronidase may be determined experimentally based on the activities of the carriers and the desired characteristics of the formulation, such as stability [0165]. The pharmaceutical composition of Jansson comprises from about 5 mg/ml to about 180 mg/ml of antibody [0264]. The antibody formulation comprises a histidine buffer, a hyaluronidase, a non-reducing dissacharide, non-ionic surfactant, anti-oxidant [0012], and hyaluronidiase PH20 ([0012],[0117]), as in instant claim 1. The formulation has a pH of about 5.5 [0012], as in instant claims 1-3.
Jansson teaches a liquid formulation comprising [0508]:
a. An antibody at concentrations of 1-180 mg/ml (vs instantly recited 20-200 mg/ml); which teaches the dosage of instant claims 1, 13-18, 23-34, 44-48)
b. Histidine buffer at concentration 5-50 mM (vs instantly recited 5-20 mM buffer); which teaches the buffer requirements of instant claims 1, 4-5, 23-34, and 58-61
c. Sorbitol at concentration of 50-400 mM [vs instant recited sucrose concentration of 3-10% (i.e. 87.6-292 mM) of instant claims 1, 6-7, 23-34, and 58-61]
d. Polysorbate 20 at concentration 0.01-0.1% (vs instantly recited 0.005-0.1% non-ionic surfactant polysorbate 80), which teaches the non-ionic surfactant requirement of claims 8-10, 23-34, 60-61, and 62
e. Methionine at a concentration 0.1-2.5 mg/ml [vs instantly recited antioxidant concentration of 1-30 mM (i.e. 0.15-4.48 mg/ml]; which teaches the antioxidant concentration of instant claims 11-12, 23-34, 58-61, and 63
f. rHuPH20 at 50-5,000 U/ml (vs instantly recited 0.0009-0.050 mg/ml or 300-17,667 U/ml), which teaches the PH20 of instant claims 1, 19-34, 52-55, and 58-59
Given that Rosengren teaches a pharmaceutical composition comprised of the anti-PD1 antibody pembrolizumab and a hyaluronidase and further given that Jansson teaches high antibody concentration formulations comprised of the same claimed excipients and overlapping concentrations of antibody and hyaluronidase, it would have been obvious to one of ordinary skill in the art to modify the formulation of Rosengren to include the concentrations of excipients, antibody, and hyaluronidase taught by Jansson. This is because both Rosengren and Jansson are both directed to high concentration antibody formulations. One would substitute the antibody of Jansson with the antibody of Rosengren and have a reasonable expectation of successfully developing an antibody formulation.
Claim 43 recites the limitation wherein the formulation is stable when stored at 5 °C for 3 months. “Stable” as defined in the specification is a formulation in which the protein therein essentially retains its physical stability, chemical stability, and/or biological activity upon storage (pg 18 of specification). Jansson teaches that the antibodies exhibited stability comparable to data of some commercial monoclonal antibody formulations [0654]. Jansson teaches that the formulation comprised of 100 mg/ml antibody, 500 U/ml hyaluronidase, histidine, sorbitol, polysorbate 20, methionine, pH 5.5) has a HMW species percentage of 1.30% at 6 months when stored at 5 °C (see Table 14), as in the limitation of claim 43 directed to %HMW is less than 2%.
Rosengren in view of Jansson does not teach a formulation comprising PH20 consisting of: amino acid residue substitutions T341 S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L3520, L353A, L354I, D355K, N356E, E359D and I361T in SEQ ID NO: 21; an N-terminus deletion of amino acid residues 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, or 1-42 of SEQ ID NO: 21; and a C-terminus deletion of amino acid residues 466-509, 467-509, 468-509, 469-509, 470-509, 471-509, 472-509, 473-509, 474-509, 475-509, 476-509, 477-509, 478-509, 479-509, 480-509, 481-509, 482-509, 483-509, 484-509, 485-509, 486-509, 487-509, 488-509, 489-509, 490-509, and 491-509, wherein the numbering is by reference to SEQ ID NO: 21.
Park teaches engineered hyaluronidase PH20 variants, with amino acid substitutions of T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T [0098], as in instant claims 1.
Park teaches that the PH20 variant may be one in which cleavage occurs before an amino acid residue selected from the group consisting of M1 to P42 at the N-terminus of the amino acid sequence of SEQ ID NO: 1 (which is identical to instant SEQ ID NO: 21), as in instant claims 1 and 52. An additional cleavage occurs after amino acids V455 to S490, such that amino acids are deleted from the C-terminus, as in instant claims 1 and 53-54.
Park teaches a PH20 variant of SEQ ID NO: 99, which is identical to instant SEQ ID NO: 23 of claim 55 and new claims 64-70.
Given that Rosengren in view of Jansson teaches formulations comprised of pembrolizumab, PH20, and the recited excipients and further given that Park teaches variant of PH20 comprised of the same amino acid substitution and deletions as those claimed, it would have been obvious to the ordinary artisan to substitute the hyaluronidase of the antibody formulation of Rosengren in view of Jansson for the PH20 variant of Park. The motivation to do comes from Park, which teaches that the PH20 variant has increased enzymatic activity and thermal stability compared to wildtype PH20 [0088]. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)."
Although Rosengren in view of Jansson and Park are silent regarding the viscosity of the formulation of claims 39-42 and the % HMW as measured by HP-SEC of claim 43, it is clear that the claimed composition would have the same viscosity as the composition taught by Rosengren in view of Jansson and Park regarding viscosity because there is no evidence to the contrary. The differences between the prior art composition and the corresponding composition disclosed in the instant claims are not substantially different. The composition of claim 1 is comprised of the same antibody and excipients at overlapping concentrations as those of Rosengren in view of Jansson and Park. Note that rejections for obviousness are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not an obvious variant; see MPEP § 2112(V).
Based on the combination of these references, it would have been obvious to the ordinary artisan to adapt the antibody formulation of Jansson to include the antibody of Rosengren and the PH20 variant of Park. The instant formulation comprises components that are routinely used and are at concentrations that are typical of those routinely used in the art for preparation of pharmaceutical antibody formulations. The art teaches antibody and hyaluronidase concentrations that fall squarely within the claimed ranges. Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to select the recited carriers, excipients, surfactants, and stabilizers of Jansson in the combination treatment of Rosengren and adjust their concentrations as needed to produce a stable pharmaceutical formulation for the anti-PD-1 antibody. One of ordinary skill in the art at the time the invention was made would have been motivated to do so, in view of the art-recognized need to optimize formulations of therapeutic antibodies with improved stability, and have a reasonable expectation of success, based on the knowledge and skill in the art and in view of the routine nature of the experimentation involved. This is because antibodies used in humans for subcutaneous delivery should be formulated to reduce antibody aggregation and optimize efficacy.
Therefore, given that combination of the claimed components and the antibody pharmaceutical formulation had been previously described, without specific evidence in the specification that the indicated concentrations and pH are critical to the formulation, the identification of these properties do not render the subject matter patentable.
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 amounts of the components recited within the claims is critical over the prior art or that there is an express teaching away.
Response to Arguments
Applicant's arguments filed November 17, 2025 have been fully considered but they are not persuasive.
Regarding the rejection of the claims under 35 U.S.C. 103 over the teachings of Rosengren in view of Jansson, applicant asserts that antibodies with different CDR regions present surface-exposed amino acids with unique interfacial surface structure, and thus the specific formulation components to provide stability and retention of activity are unpredictable (remarks, pg 16). Applicant is directed to Kang et al, entitled “Rapid Formulation Development for Monoclonal Antibodies” (instant PTO-892), which is an evidentiary reference for response to arguments and is not cited as a new reference in the rejection. Kang et al teaches a rapid platform strategy for formulation development of monoclonal antibodies (pg 40, column 1); steps include identifying optimal pH, screening of stabilizing excipients, and evaluating in-depth stabilizing buffers and excipients (pg 41, columns 1-3). Using this method, a stable formulation for monoclonal antibody can be developed in just a few weeks (pg 52, column 1). Thus, even though every antibody is unique, because their structures are similar, known successful antibody formulations can guide the development of stable and effective formulations for other monoclonal antibodies (pg 40, column 2). The amount of experimentation necessary to development a formulation for a given antibody is not considered undue, as determining the pH and components are a part of routine optimization; the claimed formulation is obvious over the prior art teachings.
Routine optimization is comprised of methods that are well-understood and conventional activities previously known to the industry. When considering whether the determination of the optimum or workable ranges of a variable (e.g., concentration of an excipient) might be characterized as routine experimentation, the particular parameter must first be recognized as a result-effective variable (see MPEP 2144.05(I)-(II). KSR International Co. v. Teleflex held that “obvious to try” was a valid rational for an obviousness finding when the invention is directed to a result-effective variable. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the concentration of excipients for an anti-PD-1 antibody and hyaluronidase formulation, because Janssen recognizes the concentration of these excipients as result-effective variables. See MPEP 2144.05.III.A, which states that applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thus, the burden is on the applicant to demonstrate that the concentration of the excipients shows unexpected results over the previously taught ranges. Types of unexpected results include greater than expected results, superiority of a property shared with the prior art, presence of an unexpected property, or absence of an expected property (see MPEP 716.02(a)I.
Regarding Rosengren, applicant asserts that no formulation or stability experiments were exemplified in the example to demonstrate why one would select a specific antibody from a laundry list of anti-PD-1 antibodies and antibody concentrations (remarks, pg 17). These arguments are not persuasive because the claimed species is clearly named by Rosengren. As Rosengren teaches immune checkpoint inhibitors in combination with hyaluronidase and Park teaches the specific hyualuronidase, it would be obvious to substitute the PH20 variant of Park for the hyaluronidase of Rosengren. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. No specific teaching suggestion is needed for combination – the idea of combining them flows logically from they having been individually taught in the prior art as useful for the same purpose. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
Applicant argues that rHuPH20 and the claimed PH20 variant fragment have different protein folding, and one skilled in the art would not turn to the excipient conditions of Janssen when formulating a composition (remarks, pg 17). Furthermore, the formulation of Janssen exhibits some undesirable results regarding thermal stress conditions, and applicant argues that one of skill in the art would not adapt the antibody formulation of Janssen for a composition comprising the claimed hyaluronidase and anti-PD-1 antibody (remarks, pg 18).
The assertion that one of ordinary skill in the art would have had no expectation of success for pharmaceutical composition of Janssen with the antibody of Rosengren cannot be accepted since the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). There is no evidence of record that supports the assertion that the ordinary artisan would not adapt the Janssen formulation.
Park teaches the claimed PH20 variant and pharmaceutical compositions thereof, which may be comprised of components that are typically used in the formulation of drugs, including sucrose and other excipients [0147]. The compositions may be combined with immune checkpoint inhibitors [0152]. There is no evidence that formulating the claimed PH20 variant taught by Park requires any special consideration related to its structure or functional properties. Furthermore, the instant composition is comprised of excipients that are commonly used in the art of antibody formulation. Although Rosengren and Janssen do not explicitly recite the composition of the instant pharmaceutical formulation, liquid formulations for antibodies are well known in the art, as taught by Rosengren and Jansson. Compositions comprising a buffer, sugar, polysorbate, and antibody at the concentrations recited were standard at the time the instant application was file. Therefore, it would be expected, absent evidence to the contrary, that providing the antibody of Rosengren in a formulation comprising excipients taught by Rosengren and Jansson would provide a successful pharmaceutical composition for intravenous administration of anti-PD-1 antibody pembrolizumab with the PH20 variant. The determination of pH and specific combinations of common components in the instant composition, including the buffer, surfactant, and stabilizer concentrations, requires only routine experimentation for one of ordinary skill in the art. Therefore, given that combination of the claimed components has been previously described, without specific evidence that the indicated concentrations and pH are critical to the formulation, the identification of these properties will not render the subject matter patentable. MPEP § 2144 sets forth Applicant's burden for rebuttal of a prima facie case of obviousness based upon routine optimization. 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Conclusion
No claim is allowed.
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.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675