DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after January 05, 2024, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 01/05/2024 in the matter of Application N° 18/576,866. Said documents are entered on the record. The Examiner further acknowledges the following:
Thus, claims 1-19 represent all claims currently under consideration.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Qiaoyu et al. (WO2020192693A1), in view of Lillian et al. (ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers).
Regarding claims 1, 2, 5, 11, 14, 16, Qiaoyu et al. disclose a pharmaceutical preparation consisting of a combination of a surfactant, a recombinant humanized anti-Her2 monoclonal antibody-MMAE conjugate, and a nonreducing sugar. The pharmaceutical preparation offers features including enhancing the freeze-dried powder’s appearance (See Abstract). additionally, mannitol and sucrose are the non-reducing sugars present in the aqueous liquid pharmaceutical preparation prior to the drug being lyophilized (See summary of the invention, paragraph 14). The appearance and molding stability of the lyophilized powder of the formulation were evaluated in accordance with the formula designed in table 10 (See example 6: Formulation screening, and table 10). The recombinant humanized anti-Her2 monoclonal antibody-MMAE conjugate generated by coupling, after purification, has low solubility in conventional buffers, and visible insoluble particles will arise that do not conform to the injection, according to the preliminary investigations (See bottom of table 3, paragraph 3). Qiaoyu et al. also disclose sodium dihydrogen phosphate, which is a buffer salt (See Example 3, paragraph 1). The aqueous liquid pharmaceutical preparation described in any of claims 1-11, with a pH of 4.5-7, ideally 5.6-6.8. The aqueous liquid pharmaceutical preparation of any one of claims 1-12 can be freeze-dried to provide a freeze-dried pharmaceutical preparation of an antibody drug conjugate. The aqueous liquid pharmaceutical in the freeze-dried pharmaceutical preparation of claim 13 contains approximately 10mg/ml of anti-Her2 monoclonal antibody-VC-MMAE, pH 5.6-6.
However, Qiaoyu et al. do not disclose wherein the freeze-dried composition comprises ARX788.
Lillian et al. disclose wherein ARX788 is a next-generation, site-specific anti-HER2 ADC that produces a homogenous ADC with a drug-to-antibody ratio of 1.9 by using a special nonnatural amino acid, facilitated conjugation technique, and a noncleavable Amberstatin drug-linker. In HER2-high and HER2-low expression xenograft models, ARX788 often performed better than T-DM1 and dramatically reduced tumor development (See Abstract).
It would have been obvious to one of ordinary skill in the art before the instant effective filing date to substitute the anti-HER2 ADC disclosed by Qiaoyu et al. with ARX788 as taught by Lillian et al. in the freeze-dried pharmaceutical preparation of Qiaoyu et al. this modification represents the predictable use of a known anti-HER2 ADC having improved homogeneity and controlled DAR in a conventional freeze-drying formulation system already established for stabilizing ADCs. A person of ordinary skill in the art would have been motivated to make this substitution because ARX788 is expressly designed to improve ADC uniformity, stability, and therapeutic performance, and Qiaoyu et al. teach that freeze-dried formulations containing surfactants and non-reducing sugars are suitable for stabilizing anti-HER2 ADCs. The use of a non-reducing sugar and surfactant would reasonably be expected to provide similar stabilization benefits when applied to ARX788, particularly in view of its antibody-based structure.
The substitution of one known anti-HER2 ADC for another known anti-HER2 ADC for another known anti-HER2 ADC in an otherwise conventional freeze-dried pharmaceutical composition would have constituted routine optimization and design choice, yielding no unexpected results.
Regarding claims 3, and 12, Qiaoyu et al. disclose sodium dihydrogen phosphate, which is a buffer salt (See Example 3, paragraph 1). Protein conditions can be improved by adding polysorbate 80 and sucrose. To protect the protein, decide how much sucrose to add to the formulation. In order to increase the protein’s solubility, decide how much polysorbate to apply (See Example 4, Table 9 (paragraph 2). Protein aggregation can be enhanced by adding polysorbate 80 and sucrose, but adding glycerol will cause the lyophilized product to shrink and collapse the aqueous solution after rebuilding. Both before and after freeze drying, the anti-Her2 man-MMAE conjugate can dissolve, and the material’s coupling is stable for a considerable amount of time both during freeze drying and storage (See Table 16, and at the bottom of table 16, refer to Description paragraphs 4, and 6). The non-reducing sugar is selected from sucrose, trehalose or a combination thereof (See claim 1).
Regarding claims 6, 7, 8, and 9, Qiaoyu et al. disclose Freeze-drying conditions: pre-freezing: temperature -45°C, time 5 hours; one-time drying: temperature -26°C, time 40 hours, vacuum degree 10-15Pa; secondary drying: temperature 25°C, time 10 hours, vacuum degree 10-15Pa (See Example 5, vacuum freeze-drying method).
Regarding claims 4, 13, and 15, Qiaoyu et al. disclose in certain embodiments, the aqueous liquid pharmaceutical formulation indicated above is freeze-dried to produce the freeze-dried pharmaceutical formulation. Additionally, approximately 10mmol/L of histidine hydrochloride, approximately 10 mg/ml of anti-HER2 monoclonal antibody-VC-MMAE, and 0.02% (W/V) of tween 80 are present in the aqueous liquid pharmaceutical preparation prior to the drug’s lyophilization (See summary of the invention, paragraphs 11 and 12). The histidine concentration is: 0-100mmol/L, preferably 5-50 mmol/L. The mass percentage of Tween 80 is: 0-0.02% (W/V) (See summary of the invention, paragraphs 3, and 4). The concentration of the anti-HER2 monoclonal antibody-VC-MMAE is 5-30 mg/ml (See summary of the invention, paragraph 6). The aqueous liquid pharmaceutical in the freeze-dried pharmaceutical preparation of claim 13 contains approximately 10mg/ml of anti-Her2 monoclonal antibody-VC-MMAE, pH 5.6-6.
Regarding claims 10, 17, 18, and 19, Qiaoyu et al. disclose the preparation of a medicine for therapeutically managing diseases caused by abnormal expression of HER2. Further preferably, the disease brought on by an abnormal expression is cancer; further preferably, the cancer is Her2 positive; further preferably, the Her2 positive cancer is lung cancer, breast cancer, urothelial cancer, ovarian cancer, esophageal cancer, uterine cancer, endometrial cancer, and bladder cancer (See summary of the invention, paragraph 14, and claims). The use of the pharmaceutical preparation according to any one of claims 1-17 in the preparation of a medicine for treating diseases caused by abnormal expression of Her2 the disease caused by abnormal expression is further preferably cancer; refer to the cancers above.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Barber whose telephone number is (703) 756-5302. The examiner can normally be reached on Monday through Friday from 6:30 AM to 3:30 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax, can be reached at telephone number (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615