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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 24, 2026 has been entered.
Claims Status
Claims 1-13, 15-36, 43, 45-48, 52-55, 58-70 and new claims 71-77 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 24, 2026 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Withdrawn Objections/Rejections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 39-42 is rendered moot by applicant’s cancellation of said claims.
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, 43, 45-48, 52-55, 58-70 and new claims 71-77 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”; IDS from 1/27/2026) 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 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 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 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 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 [0124], which is identical to instant SEQ ID NO: 23 of claim 55 and 64-70.
Park also teaches that that the PH20 variant can be used for combined treatment with immune checkpoint inhibitors [0152], as in instant claim 1.
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 enzymatic activity of the PH20 variant fragment after 3 months of storage at 25°C of new claims 71-74 the % HMW species and % monomer at 6, 3, or 1 months at 5°C, 2-8°C, and 25°C, it is clear that the claimed stability features as the composition taught by Rosengren in view of Jansson and Park 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 April 24, 2026 have been fully considered but they are not persuasive. Applicant cites Viola et al (Exhibit 1) to support arguments that the development of high antibody concentration formulations is challenging and that there is no universal formulation excipients; what might stabilize one antibody might not stabilize another (remarks, pg 14). Further, applicant asserts that Rosengren in view of Jansson and Park provide no specific direction for successfully formulating the claimed antibody and PH20 variant fragment, and that the various combinations of Rosengren render a large number of distinct compositions (remarks, pg 15). These arguments are not persuasive. One of ordinary skill in the art would modify the formulations of Rosengren, Jansson, and Park and have a reasonable expectation of successfully developing a formulation comprising an anti-PD-1 antibody and PH20, because Rosengren, Jansson, and Park recognize that concentrations of these excipients are result-effective variables, which can be determined by routine optimization (MPEP 2144.05(I)-(II)). The court has held that a claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful (MPEP 2143.02.II).
The determination of the composition and concentration of the formulation is well within the ability of those skilled artisans. Further, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,219 (CCPA 1980). When other methods similar to a claimed method have been successful, the court has determined there would have been a reasonable expectation of success. For example, in Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003), a reasonable expectation of success was found for a method of producing a particular protein when several other proteins had been produced in a similar way. The concentrations of the antibody, PH20, and excipients of the formulation are not dissimilar from those taught by the prior art; the examiner finds that the claimed formulation was determined by routine methods using method known in the art.
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 Jansson 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 filed. 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 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). That which is claimed is merely the optimization of variables within the claims that flow from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325, 1330 (Fed.Cir.2003). 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). The rejections under 35 U.S.C. 103 are maintained.
Applicant provides evidence that the PH20 variant fragment by itself showed decrease enzymatic activity in a formulation at 25 °C for 3 months, whereas PH20 co-formulated with pembrolizumab exhibited maintained enzymatic activity at 25 °C for 3 months (AK05 of Figure 9 of the disclosure; remarks pg 15). Based on this finding, applicant asserts that the claimed invention is not obvious over Rosengren, Jansson, and Park. The applicant argues that the present invention is based on the unexpected finding that the activity of PH20 is increased at 25 °C for 3 months when co-formulated with pembrolizumab. This is not found persuasive because the scope of the instant claims do not require this feature. The evidence of unexpected results must be commensurate in scope with the claimed invention (see MPEP §716.02(d)). Evidence pertaining to secondary considerations must be taken into account whenever present; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (fed. Cir. 2007) (see MPEP §2145).
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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