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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/15/2025 has been entered.
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 .
Claim Status
Claims 12, 15-16, 21, 26 and 29-43 are pending and under examination.
Rejections Maintained
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 12, 15-16, 21, 26, 29-43 remain rejected under 35 U.S.C. 103 as being unpatentable over Eriksson (US2017/0281769A1, published 10/05/2017, PTO-892 09/30/2024) in view of Zheng (WO2017/211319A1, published 08/06/2017, PTO-892 09/30/2024) and Lam (U.S. Pat. No. 6,171,586, published 01/09/2001, PTO-892 09/30/2024).
The disclosure of Eriksson is directed to stable, low viscosity antibody formulations comprising a high concentration of anti-IL4Rα antibody. Eriksson discloses various embodiments and experiments for antibody formulations and provides data and guidance for the use of different excipients in high antibody concentration formulations.
Regarding claim 12, pertaining to a liquid composition comprising an antibody against human interleukin-4 receptor alpha, a buffer, a protecting agent and surfactant, Eriksson is directed to anti-IL4Rα antibody formulations comprising excipients such as viscosity modifiers, non-ionic surfactants, and buffers ([0003], Lines 1-10) and discloses that the antibody of the disclosure may be formulated in liquid ([0599], Lines 1-2).
Regarding claim 12, wherein the antibody is present at a concentration of 100-165 mg/ml; the buffer is histidine hydrochloride at a concentration of 5-10 mmol/L; the protective agent is trehalose at a concentration of 60-150 mmol/L and sodium chloride at a concentration of 80-120 mmol/L; the surfactant is polysorbate 80 at a concentration of 0.01-0.2% (w/v); and the liquid has a pH of 5.4-6.4,
Eriksson discloses a stable high antibody concentration formulation comprising 100-200 mg/mL of anti-hIL-4Rα antibody (Pg. 165, reference claim 31), the antibody formulation comprises about 10-40mM L-histidine hydrocholoride (Pg. 166, reference claim 48(d)), 0.002-0.2% non-ionic surfactant polysorbate 80 (Pg. 35, reference claim 1(c) and 8), pH of about 5 to 8 (Pg. 165, reference claim 40).
Regarding claim 16, wherein the liquid composition comprises the antibody at a concentration of 130-165 mg/ml, the instant claim limitation falls within the range of the antibody formulation of Eriksson which is 100-200 mg/ml (Pg. 165, reference claim 31).
Regarding claim 21, wherein the histidine hydrochloride buffer is present at a concentration of 10 mmol/L (claim 21), Eriksson discloses the antibody formulation comprises about 10-40mM L-histidine hydrocholoride (Pg. 166, reference claim 48(d)).
Regarding claim 26, wherein the liquid composition is a formulation for injection, Eriksson discloses an embodiment wherein the formulation is an injectable formulation ([0618], Lines 1-4).
Regarding claims 29 and 30, pertaining to a container comprising the liquid composition according to Claim 12 (claim 29) and a kit comprising the container and instructions for use, Eriksson discloses the invention is directed to the disclosed antibody formulations in a suitable container (Pg. 166, reference claim 49) and teaches a kit comprising the claimed antibody formulation (Pg. 39, reference claim 64).
Regarding claim 31, pertaining to a method of preventing, treating or ameliorating inflammation or allergic disease, comprising administering to a subject in need thereof the liquid composition according to Claim 12, Eriksson discloses the administration of the antibody formulation for chronic inflammatory skin disease (Pg. 165, reference claim 50).
Regarding claim 32, wherein the concentration of the antibody in the liquid composition according to claim 12 is 150 ± 5 mg/ml, the instant claim limitation falls within the range disclosed by Eriksson who discloses a stable antibody formulation comprising 100-200 mg/mL of anti-hIL-4Rα antibody (Pg. 165, reference claim 31)
Regarding claim 34, wherein the concentration of sodium chloride in the liquid composition according to claim 12 is 100 mmol/L, Eriksson discloses a liquid composition comprising 100-200 mM NaCl (Pg. 35, reference claim 19).
Regarding claims 35 and 36, wherein the concentration of polysorbate 80 in the liquid composition according to claim 12 is 0.01-0.03% (claim 35) or 0.02% (claim 36), Eriksson discloses 0.002-0.2% polysorbate 80 (Pg. 35, reference claim 1(c) and 8).
Regarding claim 37, wherein the antibody of the liquid composition of claim 12 is present at a concentration of 130-165 mg/ml; histidine hydrochloride has a concentration of 10 mmol/L; trehalose has a concentration of 60 mmol/L; sodium chloride has a concentration of 100 mmol/L; polysorbate 80 has a concentration of 0.02%; and, the liquid composition has a pH of 5.4-6.4, each of the limitations is taught in Eriksson as described in the rejections for claims 12, 16, 21, 34, and 36 above.
Regarding claim 38, wherein the pH of the composition according to the liquid composition of claim 37 is 6.2 ± 0.2, Eriksson discloses the formulation has a pH of about 5 to 8 (Pg. 165, reference claim 40).
Regarding claim 39, wherein the concentration of the antibody according to the liquid composition of claim 37 is 150 ±5 mg/ml, the antibody formulation of Eriksson is 100-200 mg/ml (Pg. 165, reference claim 31).
Regarding claim 40, wherein the liquid composition according to claim 12 is a formulation for subcutaneous injection or intravenous injection, Eriksson discloses the antibody formulation is suitable for intravenous and subcutaneous administration (Pg. 39, reference claim 59).
Regarding claims 41-43, wherein the inflammation or allergic disease according to the method of claim 31 is an autoimmune disease, allergic dermatitis, asthma, eosinophilic esophagitis, eczema, allergic rhinitis, nasal polyp, or rheumatoid arthritis, specifically eczema (claim 42) or asthma (claim 43), Eriksson discloses the method used to treat eczema (Pg. 40, reference claim 71) and asthma (Pg. 40, reference claims 70).
Eriksson does not disclose: (1) wherein the antibody comprises a light chain variable region comprising CDR-L1 set forth in SEQ ID NO: 1, a CDR-L2 set forth in SEQ ID NO: 2, and a CDR-L3 set forth in SEQ ID NO: 3, and wherein the heavy variable comprises a CDR-H1 set forth in SEQ ID NO: 5, the CDR-H2 set forth in SEQ ID NO: 6, and the CDR-H3 set forth in SEQ ID NO: 7 according to claim 12 and wherein the light chain variable region as set forth in SEQ ID NO: 4 and the heavy variable region as set forth in SEQ ID NO:8 according to claim 15 or (2) wherein the liquid composition comprises a protecting agent trehalose at 60-150 mmol/L and 60 mmol/L according to claims 12, 33, and 37.
These deficiencies are taught by Zheng and Lam.
The disclosure of Zheng is directed to the generation of antibodies specific for IL-4R. Zheng discloses the antibody clone L1020H1031 corresponding to clone CBP-201 of the instant invention.
The disclosure of Lam is directed to stable aqueous pharmaceutical formulations comprising a therapeutically effective amount of an antibody, a buffer, a surfactant, and a polyol. (Column 2, Lines 25-34). Lam teaches trehalose provides superior solution stability compared to sucrose (Column 6, Lines 59-60). Lam Fig. 28 demonstrates the stability of an antibody composition comprising 150 mM trehalose stored at 2-8°C for two years (Column 5, Lines 34-38).
Regarding claims 12 and 15, Zheng discloses the antibody clone L1020H1031/CBP-201 comprising a light chain variable region set forth in SEQ ID NO: 55 corresponding to instant SEQ ID NO: 4 and comprising instant light chain CDRs SEQ ID NO: 1, 2, and 3, respectively. The sequence alignment is shown below:
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922
558
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Zheng discloses the antibody clone L1020H1031/CBP-201 comprising a heavy chain variable region set forth in SEQ ID NO: 91 corresponding to instant SEQ ID NO: 8 and comprising instant heavy chain CDRs SEQ ID NO: 5, 7, and 6, respectively. The sequence alignment is shown below:
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418
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Zheng provides the pharmacokinetic data for the L1020H1031/CBP-201 clone showing persistence of the antibody in mice (Pg. 1, paragraph 1 and 2 translated document and Fig. 1 original document) and cynomolgus monkeys (Pg. 20 paragraph 1 translated document and Fig. 2 original document). Zheng also provides functional data demonstrating that the L1020H1031/CBP-201 clone inhibits the release of inflammatory markers thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) (Pg. 22 paragraph 1 translated document and Fig. 5A-5B original document).
Regarding the limitation of claim 12, claim 33, and claim 37 wherein liquid composition comprises a protecting agent trehalose at 80-120 mmol/L and 60 mmol/L according to claims 12, 33, and 37, Lam teaches a preferred liquid dose comprising antibody and 150 mM trehalose (Column 46, Conclusion), and optimization methods comprising trehalose ranging from 0-267 mM (Pg. 48, Table 17).
It would have been obvious to one having ordinary skill in the art to modify the anti-IL-4Rα antibody formulation of Eriksson with (1) the anti-IL-4Rα L1020H1031/CBP-201 clone of Zheng comprising the light chain variable region SEQ ID NO: 4 and heavy chain variable region SEQ ID NO: 8 and (2) 60-150 mmol/L trehalose as taught by Lam. It would have been obvious to do so because (1) Zheng provides pharmacokinetic evidence showing the antibody’s persistence in vivo and functional evidence that the clone reduces the expression of inflammatory biomarkers. In all, the clone shows promise in a pharmaceutical formulation for use in a method of treating inflammatory conditions and (2) Eriksson discloses the use of trehalose as a preferred excipient in an antibody formulation and Lam discloses optimization experimentation with 0-256 mM trehalose and optimal 150 mM concentration of trehalose as part of a stable antibody formulation. As Eriksson provides evidence of the stability of the disclosed formulations, Zheng provides evidence of the function of the disclosed anti-IL-4Rα antibody, and Lam provide several stable antibody compositions with a range of trehalose concentrations, there would be an expectation of success in combining the prior art elements to arrive at the instant invention comprising well-characterized antibodies and excipients with ranges known in the art.
Response to Applicant’s Arguments
Applicant's arguments filed 10/15/2025 have been fully considered but they are not persuasive.
The applicant makes the following arguments:
I. Applicant invokes the exception under 35 U.S.C. § 102(b)(2)(C). Applicant submits the following statement relating to the instant application (U.S. Patent Application No. 17/436,981) and Zheng, which corresponds to International Application No. PCT/CN2017/087592:
U.S. Patent Application No. 17/436,981 and International Application No. PCT/CN2017/087592 were, not later than the effective filing date of the claimed invention in U.S. Patent Application No. 17/436,981, each owned by Applicant. (Remarks, Pgs. 5-6)
In response, the exception under 35 U.S.C. § 102(b)(2)(C) does not apply in the instant case. The instant application 17/436,981 is a 371 of PCT/CN2020/079120 which has the filing date 03/13/2019. Zheng (WO2017/211319A1) was published 08/06/2017 which is a public disclosure date outside of the one-year grace period and is therefore eligible as prior art.
II. Applicant submits that there would have been no motivation to combine the cited references to produce the claimed invention, at least because Eriksson teaches away fromThe general applicability of its antibody formulations. At paragraph [0005], Eriksson states that "[d]ue to the wide variety of antibodies, there are no universal formulations or conditions suitable for storage of all antibodies. Optimal formulations of one antibody are often specific to that antibody. Additionally, antibody formulations may need to be further tailored to a specific antibody depending on the concentration of the antibody, and/or a desired physical property, e.g., viscosity, of the antibody formulation." (Remarks, Pgs. 6-7).
In response, Eriksson, Zheng, and Lam teach all of the components of the instant invention and when combined, they all function as taught in the art. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. (MPEP 2143). The specific antibody excipients at the claimed concentrations were all successfully implemented in the field of antibody pharmaceuticals. Each excipient has a specific purpose within the formulation. Importantly, the prior art references cited herein teach the disclosed formulation is suited for high concentration formulations up to 200 mg/mL.
Additionally, MPEP 2144.05 teaches the obviousness of similar and overlapping ranges, amounts and proportions. "[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) (MPEP 2144.05 II.A.). Routine optimization of antibody formulations is standard within the art.
Although there is a degree of unpredictability in antibody formulation, the optimization of antibody formulations with known excipients and within known concentration ranges is also routine within the art as evidenced by Kang (BioProcess Inernational. April 2016. 14(4), cited in PTO-892 filed 04/17/2025). Kang evaluated successful monoclonal antibody formulations ranging in concentration from 2mg/ml to 200 mg/ml and developed a database of excipients (Page 40, Middle column, Full paragraph 1). Using the established excipients, they developed a platform to quickly identify ideal pH and excipient formulations for new antibodies (Page 42 details the three-stage screening and excipient optimization process).
Kang teaches that although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang teaches lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph) and provides 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Thus, the prior art provides ample guidance for routine optimization of antibody formulations.
The examiner reaffirms the appropriateness of rejecting claims 12, 15-16, 21, 26, and 29-43 under 35 U.S.C. 103 as being unpatentable over Eriksson in view of Zheng and Lam because each component of the claimed pharmaceutical composition was known in the art and each component functioned to stabilize the antibody formulation as taught by the art.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646