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
Response to Amendment
The Information Disclosure Statement (IDS) filed 2 January 2026 has been entered. Applicant’s submission of a substitute specification in both marked-up and clean formats in compliance with 37 C.F.R. 1.52, 1.121(b)(3), and 1.125, filed 12 December 2025, is acknowledged. Applicant’s amendment of the claims filed 12 December 2025 has been entered. Applicant’s remarks filed 12 December 2025 are acknowledged.
Claims 6, 13, 15, 20-31 and 33-48 are cancelled. Claims 49-53 have been added. Claims 1-5, 7-12, 14, 16-19, 32 and 49-53 are pending. Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1-5, 7-12, 14, 16-19 and 49-53 are under examination to the extent they read on the elected species: A-a) wherein the surfactant is a polysorbate; and B) wherein the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO: 78.
Specification
The objections to the specification for: 1) containing embedded hyperlinks at paragraph [0090], and 2) missing a column header (SEQ ID NO) in the first column of Table 2, are withdrawn in response to Applicant’s amendment of the specification.
Claim Objections/Rejections Withdrawn
The objection to claim 3 for informalities is withdrawn in response to Applicant’s amendment of the claim.
The rejection of claims 1-5, 7-10, 12, 14 and 16-19 under 35 U.S.C. 102(a)(1), as being anticipated by Olbrich et al. (US 2015/0335706 A1, Pub. Date: Nov. 26, 2015), is withdrawn in response to Applicant’s amendment of independent claim 1 to require the composition contained inside a container which is made of a plastic substantially free of di-2-ethylhexyl phthalate (DEHP) or tri-2- ethylhexyltrimellitate (TOTM).
The provisional rejection on the ground of nonstatutory double patenting over the claims of copending Application No. 18/024,893 is withdrawn in response to Applicant’s amendment of the claims of the present application.
New Grounds of Objections/Rejections
Claim Objections
Claims 1, 7, 52 and 53 are objected to because of the following informalities:
In claim 1, “and polysorbate at a concentration …” should be “and a polysorbate at a concentration …”; and “free di-2-ethylhexyl phthalate (DEHP)” should be “free of di-2-ethylhexyl phthalate (DEHP)”.
Claim 7 recites “wherein polysorbate …”, which should be “wherein the polysorbate …”.
Claims 52 and 53 use acronyms without first defining what they represent (e.g., “PVC”, “EVA”). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronyms.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites “the surfactant”. There is insufficient antecedent basis for this limitation in the claim.
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 of this title, 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 1-5, 7-10, 12, 14, 16-19 and 49-53 are rejected under 35 U.S.C. 103 as being unpatentable over Olbrich et al. (US 2015/0335706 A1, Pub. Date: Nov. 26, 2015) (reference provided previously), in view of Zhu (CN 103387723 A, Pub. Date: November 13, 2013).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Olbrich teaches a liquid pharmaceutical composition comprising a polypeptide, i.e., Bispecific T-cell Engager or BiTE, wherein the polypeptide comprises two scFv antigen-binding domains, the first scFv binding domain binds to human CD3 episilon, and the second scFv binding domain binds to a cell surface antigen [0040] [0042] [0204] [0205]. Olbrich teaches that the first binding domain comprises the amino acid sequence of SEQ ID NO: 5 [0046] [0209], which is identical to SEQ ID NO: 201 of the instant application (sequence alignment provided previously). Olbrich teaches an exemplary BiTE, e.g., PSMA-BiTE1, with the amino acid sequence of SEQ ID NO: 8, which comprises SEQ ID NO: 167 of the instant application (sequence alignment provided previously). Olbrich teaches that the liquid pharmaceutical composition comprising the polypeptide in a concentration of from 0.5 mg/ml to 0.2 mg/ml [0223]. Olbrich teaches that the composition contains 0.04% polysorbate 80 [0239]. The CMC of polysorbate 80 is in the range of 0.001% to 0.006% w/v. Therefore, Olbrich meets the limitation of the surfactant (i.e., polysorbate) concentration as required in claims 1 and 7. Regarding newly added claim 49, Olbrich teaches that useful polysorbates (as a wetting agent) include polysorbate 20 or 80 in a concentration of from 0.002% to 0.1%, preferably from 0.04% to 0.1% [0089] [0090]. Olbrich teaches that the composition contains Tris and phosphate (e.g., sodium phosphate), and the composition has a pH in a range of about 5.0-7.0 [0039] [0228-0233]. Olbrich teaches that the composition additionally contains trehalose dihydrate, e.g., about 4% [0243]. Olbrich teaches that a BiTE formulation, which comprises 50 mM phosphate, 100 mM Tris, 0.04% polysorbate 80, and 4% trehalose dihydrate, at a pH of 6.0, is capable of stabilizing PSMA-BiTE1 with respect to the formation of aggregates, and this applies both to low concentrations in the range of below mg/ml and to high concentrations of >2 mg/ml [0010]. Olbrich further shows that a PSMA-BiTE1 aqueous solution diluted with 0.9% NaCl solution and containing 0.004% polysorbate and PSMA-BiTE1 at a concentration of 2 mg/ml, was stable over a storage period of 9 days (see Example 21). Olbrich teaches that the composition is suitable for as intravenous injection or infusion [0134].
Olbrich teaches as set forth above. Olbrich, however, does not teach wherein the liquid pharmaceutical composition is contained inside a container, which is made of a plastic substantially free di-2-ethylhexyl phthalate (DEHP) or tri-2- ethylhexyltrimellitate (TOTM) (claim 1), and wherein the plastic container that is substantially free of DEHP or TOTM is made of a material comprising PVC (claims 52-53)
Zhu teaches that dihexyl phthalate (DEHP)-plasticized polyvinyl chloride (PVC) has been used as the main raw material to produce disposable infusion sets, however, the safety of DEHP has attracted attention especially in the food and medical fields [0004] [0005]. Zhu teaches a number of detrimental effects that DEHP can cause in human, including cancer [0006-0009]. Zhu teaches that currently used infusion set components, such as drip bottles and tubing, are made of DEHP-plasticized PVC, which contains a large amount of DEHP; during infusion, DEHP easily dissolves in the medication and enters the bloodstream along with the medication, increasing safety risks and causing infusion-related harm to the human body [0011]. Zhu discloses a DEHP-free PVC material and infusion set made therefrom that are inert at room temperature, reducing the leaching of harmful substances, and allowing for safe and reliable use in the medical and health fields [0013] [0017].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the infusion set made from a DEHP-free PVC material for administering the liquid pharmaceutical composition of Olbrich. One of ordinary skill in the art would have been motivated to do so, because Olbrich teaches a liquid pharmaceutical composition comprising a BiTE molecule that is suitable for intravenous infusion, and Zhu teaches an infusion set made from a DEHP-free PVC material which can avoid the infusion-related harm from DEHP leached from an infusion set. Therefore, the combined teachings provide a reasonable expectation of success in treating the patient.
Claims 11 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Olbrich et al. (US 2015/0335706 A1), in view of Zhu (CN 103387723 A), and further in view of Raum et al. (US 2017/0218078 A1, Pub. Date: Aug. 3, 2017) (reference provided previously).
Olbrich and Zhu teach as set forth above. These references, however, do not teach wherein the bispecific construct further comprises a third domain comprising, in an amino to carboxyl order, hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain (claim 11), and wherein the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO: 78 (the elected species) (claim 19).
Raum teaches that the fusion of a specific Fc modality, i.e. the third domain, to a BiTE molecule comprising two scFv antigen-binding domains significantly prolonged half-life of the bispecific antibody construct ([0014-0018] [0087]). Raum teaches that the third domain comprises in an N- to C-terminal order, hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain [0079]. Raum teaches a bispecific DLL3xCD3 antibody construct set forth in SEQ ID NO: 520, which is identical to SEQ ID NO: 78 of the instant application (see sequence alignment of SEQ ID NO: 78).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a fusion between the BiTE molecule disclosed in Olbrich and the third domain taught by Raum. One of ordinary skill in the art would have been motivated to do so, because Olbrich and Zhu teach a liquid pharmaceutical composition comprising a BiTE molecule comprising two scFv antigen-binding domains, and Raum teaches that the fusion of the third domain to a BiTE molecule can significantly prolong half-life of the bispecific antibody construct. Therefore, the combined teachings provide a reasonable expectation of success in making a liquid pharmaceutical composition comprising a BiTE molecule that has a prolonged half-life.
Claim Rejections Maintained
Double Patenting
Amended claims 1, 4-5, 7-10, 12, 14 and 16-18 and 50-51 remain rejected on the ground of nonstatutory double patenting as being unpatentable over:
1) claims 1, 5-12 and 18-19 of U.S. Patent No. 11,419,933; and
2) claims 1-2, 9, 13, 22, 27-28 and 34-36 of copending Application No. 16/482,603 (this is a provisional rejection).
Applicant argues that claim 1 has been amended to recite a pharmaceutical preparation comprising an aqueous composition contained inside a container, wherein the aqueous composition comprises a bispecific antibody construct at a concentration of between about 0.001 g/ml and about 100 g/ml and polysorbate at a concentration of at least about 0.25 x of the critical micelle concentration (CMC), and wherein the container is made of a plastic substantially free di-2- ethylhexyl phthalate (DEHP) or tri-2-ethylhexyltrimellitate (TOTM), and that the Office cited no disclosure or suggestion of use of a particular surfactant with the particular container material required by the instant claims.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
The claims of the ‘933 patent and the ‘603 application recite a liquid pharmaceutical composition comprising a bispecific single chain antibody construct of the subject claims, wherein the bispecific single chain antibody construct is present in a concentration range of 0.1-5 mg/ml or 0.1-8 mg/ml, and wherein the pharmaceutical composition comprises polysorbate 80 at a concentration of about 0.01% (w/v). Regarding the plastic container for the liquid pharmaceutical composition, Zhu (CN 103387723 A, cited above) teaches and renders obvious of using a plastic container made from a DEHP-free PVC material such that it can avoid the infusion-related harm from PVC-leached DEHP (see above 103 section). Therefore, the instant claims are obvious over the claims of the ‘933 patent and the ‘603 application in view of Zhu.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/XIAOZHEN XIE/Primary Examiner, Art Unit 1674