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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/15/2025 has been entered.
Claims 52-78 are under consideration in the instant Office Action.
New Claim Objections
Claims 52-53 are objected to because of the following informalities: the instant claims recites its limitations separated by bulleted letters. See MPEP § 608.01(m), which states when a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate sub combinations or related steps.
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 52-78 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/066468 A1 (in IDS filed 10/28/2021, hereinafter “Bee”), in view of WO 2011/161226 A2 (in IDS filed 10/28/2021, hereinafter “Adler”), and Patel et al. (WO 2017/180594 A1, in instant PTO-892).
Bee discloses formulations of an antibody which are identical to the exemplified antibody “COR-001”, which comprises the instant SEQ ID NOs: 9 and 10. The antibody of Bee is a designated anti-IL-6 (YTE) and represented by SEQ ID NOs: 1 and 2 as heavy and light chain sequences respectively, see pages 13 and 14. SEQ ID NO: 1 of Bee is identical to SEQ ID NO: 9 of the instant application and SEQ ID NO: 2 is identical to SEQ ID NO: 10 of the instant application. Instant CDRs SEQ ID NOs: 1-6 are encompassed within SEQ ID NOs: 9 and 10, with SEQ ID NOs: 1-3 encompassed in SEQ ID NO: 9 and SEQ ID NOs: 4-6 encompassed in SEQ ID NO: 10.
One of the exemplary anti-IL-6 (YTE) formulations taught by Bee comprises an antibody concentration of 100 mg/ml in 25 mM histidine, 180 mM trehalose (which translates to 6% (w/v) trehalose (molecular weight trehalose: 342.296 g/Mol)), 25 mM arginine and 0.07% polysorbate 80 at pH 6.0, see Table 4. Bee also discloses a range of concentrations for arginine, spanning from 20 mM to about 400 mM, see reference’s claim 24 and paragraph 0022. The formulation was practically free from visible particles after 12 months and it was concluded that the antibody was stable in said formulation, see paragraph 0137. Bee discloses routes of administration, wherein the preferred methods are “parenteral, inhalation or topical modes of administration. The term parenteral as used herein includes, e.g., intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration”, see paragraph 102. Bee also teaches the “The colloidal and conformational stability of proteins are impacted by solution conditions such as ionic strength, pH and the presence of excipients such as disaccharides or amino acids. Surfactants are often added to protein formulations to protect against aggregation caused by interfacial stresses or to inhibit particle formation. A reduction in protein stability could occur if a formulation excipient is diluted below its necessary level. Additionally, exposure to the high ionic strength environment in saline IV bags may accelerate specific degradation pathways for some proteins. Thus, a need exists to provide high concentration antibody formulations that can overcome many of these challenges”, see paragraph 0007-0008.
However, Bee does not teach the addition of methionine to the formulation. Adler remedies this deficiency.
Adler discloses antibody formulations with very similar components to the instant application, e.g. in the reference’s claim 15 which discloses a pharmaceutical liquid formulation comprising 150 mg/ml of a human antibody, 20 mM of histidine acetate buffer at pH 5.8, 0.05 % of a surfactant, 10 mM methionine and 200 mM trehalose. The component methionine is explicitly described in the formulation to be included as a stabilizer by way of its antioxidant action (see page 5, lines 7-10) for proteins and antibodies in formulation. This meets the limitations of claims 52-53, 70-72, and 78 wherein the antibody sequences, the exact formulation for the antibody, and routes of administration are taught in the prior art.
However, Bee and Adler do not explicitly recite the benefits of adding methionine to the formulation. Patel et al. remedies this deficiency.
Patel et al. addresses the need for an invention that results in “improved pharmaceutical compositions that contain high concentrations of one or more protein biomolecule(s). In particular, the invention relates to such pharmaceutical compositions that include one or more amino acid molecules, particularly arginine, alanine, glycine, lysine or proline, or derivatives and salts thereof, or mixtures thereof, as stabilizing compounds. The inclusion of such stabilizing compounds decreases reconstitution time whilst improving and/or maintaining the long-term stability of the protein biomolecule, so as to facilitate the treatment, management, amelioration and/or prevention of a disease or condition by the pharmaceutical composition”, see Abstract. Patel et al. even recites a list of amino acids that would be successful at stabilizing the proteins of interest with methionine included, see paragraph 0009 wherein “the amino acids histidine, arginine, glutamate, glycine, proline, lysine and methionine have been mentioned as natural compounds that stabilize proteins”.
Instant claims 54-56 recite lower concentrations of the antibody in formulation, specifically in antibody concentrations of 7.5, 15, or 30 mg/mL. However, that fact does not avoid a finding of prima facie obviousness in light of the overlap of the claimed range. “Selecting a narrow range from within a somewhat broader range disclosed in a prior art reference is no less obvious than identifying a range that simply overlaps a disclosed range.” In re Peterson, 315 F.3d at 1329—30. Because a skilled person in the art would attempt to identify the optimal treatment dose amount and dosing schedule for an antibody when used therapeutically and would adjust the dose accordingly to reach the optimum dosing strategy, the method of instant claims 54-56 is obvious over the teaching of Bee and Adler. “(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, 220F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Since antibody stability, and especially antibody aggregation, is clearly dependent on the concentration of the antibody, the indication of such relatively low antibody concentrations does not fit in line with the expectation of optimization as the instant disclosures and the prior art which are directed towards higher concentrations of antibodies and optimizing a formulation for such.
Instant claims 57-69 recite functional properties of the claimed antibody when placed in the formulation. Since the exact antibody and formulations are taught in the prior art and the instant claims recite functional properties of the antibody which are inherent to the structure, it would reasonable for one of ordinary skill in the art to expect these various conditions to arise after storage in the taught formulations when the specific conditions are tested for. Instant claims 73-77 recite intended uses and routine applications of the claimed antibody formulations and thus are included in the rejection.
It would be obvious at the time of the instant invention to use the antibody and formulation taught by Bee, which is an anti-IL-6 antibody stored in an optimized formulation that results in stability for the antibody, with the addition of methionine taught by Adler, which serves as an antioxidant that protects against the oxidation of proteins such as antibodies when stored in solution, with the teachings of Patel et al. which discuss the importance of adding methionine to a formulation to aid in keeping the proteins stable. One would be motivated to combine the antibodies in this particular formulation with the addition of methionine with the expectation of protecting against oxidation and enhancing the stability of the proteins, in particular antibodies, in a long-term formulation that is suited for therapeutic applications.
Therefore, claims 52-78 are rejected as obvious over Bee, Adler, and Patel.
Response to Arguments
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive.
Applicant argues “the combination of Bee and Adler is insufficient to meet the requisite threshold of prima facie obviousness by giving the skilled artisan a reason to combine the references as required by the KSR court”. This is not found persuasive.
Bee teaches the solution conditions that impact the colloidal and conformational stability of proteins, “such as ionic strength, pH and the presence of excipients such as disaccharides or amino acids. Surfactants are often added to protein formulations to protect against aggregation caused by interfacial stresses or to inhibit particle formation”, see paragraph 0007. Bee discloses the addition of a variety of amino acids, including arginine and histidine, to improve the stability of the proteins in formulation (see paragraph 0007) with the motivation for using amino acids in formulation as addressing “the existing need to provide high concentration antibody formulations that can overcome many of these challenges [aggregation]. Additionally, a need exists for a method of adding an antibody formulation to an IV bag, wherein the antibody formulation does not degrade, precipitate, or otherwise loose efficacy during dilution”, see paragraph 0008. The teachings of Bee set up a motivation for the addition of amino acids, amongst other excipients and conditions, that one of ordinary skill in the art would recognize as being useful to modify and optimize when seeking to reduce protein aggregation. Adler then addresses this same motivation of reducing protein aggregation in formulation by teaching a very similar formulation to the one disclosed in Bee, but this time with the addition of methionine. Adler specifically address the addition of methionine to the formulation in “the component methionine is explicitly described in the formulation to be included as a stabilizer by way of its antioxidant action (see page 5, lines 7-10) for proteins and antibodies in formulation”. As such, both references address the same rationale of using a variety of amino acids to stabilize the proteins whilst in formulations.
The inclusion of Patel et al. addresses the need for an invention that results in improved pharmaceutical compositions that contain high concentrations of protein biomolecules. Patel et al. explicitly recites that amino acids are great additions to a formulation to address this characteristic, and describes a list of amino acid molecules, particularly arginine, alanine, glycine, lysine or proline, or derivatives and salts thereof, or mixtures thereof, as stabilizing compounds. Patel et al. even recites a list of amino acids that would be successful at stabilizing the proteins of interest with methionine included, see paragraph 0009 wherein “the amino acids histidine, arginine, glutamate, glycine, proline, lysine and methionine have been mentioned as natural compounds that stabilize proteins”. Patel et al. teaches that the inclusion of such “stabilizing compounds decreases reconstitution time whilst improving and/or maintaining the long-term stability of the protein biomolecule, so as to facilitate the treatment, management, amelioration and/or prevention of a disease or condition by the pharmaceutical composition”, see Abstract. As evidenced by the prior art, one of ordinary skill in the art would recognize that Bee disclosed, at the time of the instant invention, the proper motivation for the ways in which protein stability could be improved by the addition of amino acids, and Adler explicitly listed “methionine” as the amino acid that could be substituted into a similar formulation for high concentration antibodies, and Patel et al. connects these dots firmly with a rationale to use methionine in a formulation. As such, one of ordinary skill in the art would find the motivation to add methionine to the formulation as taught by Patel et al. in a way to better stabilize the proteins.
The instant claims are amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant claims, given the teachings of the prior art, it would have been obvious to combine the teachings of Bee and Adler because the idea of doing so would have logically followed from their having been individually taught in the prior art to be have disclosed, at the time of filing, the addition of excipients in the form of amino acids to aid in protein stabilization. One of ordinary skill in the art would have reasonably expected to obtain a benefit upon the combination of the additional excipients since they had been demonstrated in the prior art to be reasonably successful in reducing protein aggregation while formulations are kept in storage.
Applicant argues that “the Federal Circuit explicitly directs that a prior art reference must be read as a whole in its entirety, not just selected portions or isolated sentences” and “Adler must be used for all that it teaches. Here, the Examiner has chosen to impermissibly rely on only the portion of Adler where methionine was used and turn a blind eye to the remaining teachings of the reference where methionine was not used”. This is not found persuasive.
The Examiner has considered the teachings of the references as a whole. As is custom in rejections based on the prior art, such rejections focus on aspects of the reference that teach the claim limitations. Applicant is reminded that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). Additionally, Applicant’s claim that the Examiner has ignored teachings in portions of Adler that fail to mention methionine are not relevant. The instant claim limitations regarding the addition of methionine are limitations that were found in some embodiments of Adler, which were then used in the instant rejection. As discussed above, one of ordinary skill in the art would be motivated to include the addition of amino acids to high concentration antibody formulation to prevent aggregation and assist in the maintenance of protein stability when stored. The teachings of the prior art demonstrate that the addition of amino acids, like methionine, reduce oxidative stress on the proteins and thus are optimal additions to formulation. This is in line with the limitation described by the claim, and thus rejected. The Examiner considered the teachings and embodiments that do not describe the addition of methionine, but ultimately did not use them in the rejection as it was known at the time of filing that methionine improved protein stability, and thus was in line with the instant claim limitations. Additionally, the instant claims required the addition of methionine. Using embodiments that fail to recite a required limitation would not meet the claim limitations as recited by Applicant and thus were not used in the rejection.
Therefore, the rejection is maintained.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675