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 .
Election/Restrictions
The restriction requirement is made final.
Response to Amendment
The rejection of claims 2, 3, 5, 7, 10-12, 22 and 26 are moot in view of the cancelation of the claims. Note that the limitation of claim 26 has been added to claim 1 by amendment. Limitations encompassed by claims 2, 3, 5, 7 and 10-12 have also been added to claim 1.
The provisional rejection of claims 1, 2, 5, 7, 10-12, 14, 15, 22 and 26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 24 and 28 of copending Application No. 17/262,962 (‘962, reference application) is withdrawn in view of the abandonment of the copending application.
The provisional rejection of Claims 1, 2, 5, 7, 10-15, 22 and 26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 24 and 28 of copending Application No. 16/482,603 (‘603, issued as US Patent 12,617,853) is withdrawn in view of the claim limitations of ‘603 and now its issued patent, wherein the pH is required to be in the range of 4.0-5.0, and amendment to instant claims requiring a pH of 5.2.
The provisional rejection of Claims 1, 5, 7, 10-12, 14, 15, 22 and 26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 38, 43, 46, 62 and 64-68 of copending Application No. 16/964,452 (‘452, reference application) is withdrawn in view of the claim limitation of the copending application wherein the pH is required to be in the range of 4.2-4.6, and amendment to instant claims requiring a pH of 5.2.
The provisional rejection of Claims 1,5, 7, 10-22 and 26 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, 8, 11, 12, 15, 16, 18 and 20-29 of copending Application No. 17/921,794 (‘794, reference application) is withdrawn in view of the claim limitation of the copending application wherein the pH is required to be in the range of 4.5 (or 4.2--see claim 20) and amendment to instant claims requiring a pH of 5.2.
The provisional rejection of Claims 1, 2, 5, 7 and 10-12 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 30-41, 45, 50 and 51, 43, 46, 62 and 64-68 of copending Application No. 19/022,064 (‘064, reference application) is withdrawn in view of the claim limitation of the copending application wherein the pH is required to be in the range of 3.5 to 5 and amendment to instant claims requiring a pH of 5.2.
The provisional rejection of claims 1, 2, 5, 7, 10-15, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 22, 24, 25, 27 and 28 of copending Application No. 19/024,641 (‘641, reference application) is withdrawn in view of the claim limitation of the copending application wherein the pH is required to be in the range of 4.0 to 5.0 and amendment to instant claims requiring a pH of 5.2.
Claims 1-3, 5, 7, 10-12, 14-17, 19, 22 and 26 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,918,650 B2 (‘650) in view of the amendment to instant claims requiring the absence of a preservative.
The rejection of Claim(s) 1 and 13-21 under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 11,918,650 B2 (‘650) in view of the amendment to claim 1 requiring the absence of a preservative, which ‘650 teaches away from.
The rejection of Claim(s) 1-3, 5, 7 and 10-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/204907 A1 (Abel, cited in the IDS filed 9/29/2023) in view of the amendment to claim 1 requiring a formulation pH of 5.2 in combination with the formulation components and HMW limitation. The reference does not anticipate amended claim 1 or the dependent claims thereof.
Claim(s) 1-3, 5, 7 and 10-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/021349 A1 (Raum) in view of the amendment to claim 1 requiring a formulation pH of 5.2 in combination with the formulation components and HMW limitation. The reference does not anticipate amended claim 1 or the dependent claims thereof.
Claim Interpretation
As amended, claim 1 recites the bispecific antibody comprising a first binding domain that binds a cell surface antigen and a second binding domain that binds human CD3, “wherein the binding domains are two single-chain variable fragments joined by a linker”. It reasonably appears this refers to the binding domains together being two scFv joined by a linker (see the specification in the middle of paragraph [0069]).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14 and 15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. It reasonably appears claims 14 and 15 were intended to depend ultimately from claim 1*, which has been amended to recite for the bispecific antibody construct “wherein the binding domains are two single-chain variable fragments joined by a linker”. Therefore, it reasonably appears that the limitation of claim 14 drawn to wherein the first and second binding domains comprise a VH and VL region and of claim 15 drawn to wherein the bispecific antibody construct is a single chain antibody no longer further limits claim 1 as it has been amended. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
*In the interest of compact prosecution, it is being assumed that claim 13 was intended to depend from claim 1 since the limitation from claim 12 has been added to claim 1 and claim 12 has been canceled. (See rejection under 35 USC 112(b) below.)
Claim Rejections - 35 USC § 112(b)
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.
Claims 13, 16-21 and dependent claims 14-15 are 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.
Claims 13 and 16-21 are indefinite because they depend from canceled claim 12. Claims 14-15 depend from claim 13.
In the interest of compact prosecution, it is being assumed that claims 13 and 16-21 depend from claim 1 since the limitation from claim 12 has been added to claim 1 and claim 12 has been canceled. However, the rejection must be addressed.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 13-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 has been amended to recite the limitation ”wherein the formulation does not comprise a preservative”. There is no basis in the specification for this negative limitation. There is nothing in the specification to reasonably suggest the inventors specifically excluded a preservative from the claimed aqueous pharmaceutical formulation. Note that in claim 1 the word “comprising” is used to describe the contents of formulation instead of “consisting of”, which would exclude non-recited components. As stated in MPEP 2173.05(i), “Any negative limitation or exclusionary proviso must have basis in the original disclosure.” Neither the specification nor the claims as originally filed support the negative limitation.
Claims 1 and 13-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Because the limitation of now cancelled claim 26 was brought into claim 1 in the amendment filed 7/10/2026, the rejection of claim 26 has been recast as it relates to amended claim 1 and claims depending from claim 1.
Claim 1 is drawn to an aqueous pharmaceutical formulation comprising (a) a bispecific antibody construct, (b) sucrose, (c) polysorbate 80, and (d) a glutamate buffer, wherein the pH is 5.2. There are no specific amounts or concentrations of (b)-(d) recited in claim 1. The bispecific antibody in claim 1 has been amended to be described as having two binding domains, wherein the first binds a target cell surface antigen and the second binds human CD3 and wherein the binding domains are two single chain variable fragments joined by a linker. Claim 1 further limits the formulation as comprising less than 5% of high molecule weight (HMW) aggregates of the bispecific antibody construct after storage at 40˚C for one month.
To obtain a HMW aggregation of less than 5% for a bispecific construct at 40˚C after one month (claim 26), the same six conditions used in Example 6 for determining % LMW were used with BiTE®-G and -D. For % HMW, all BiTE®-G- or -D-containing formulations: 10 mL L-glutamic acid, 9% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2, met the limitation ({0159] and Tables 5 and 6). That the required % HMW could be obtained with a glutamate and acetate buffer formulation that was otherwise identical, does not mean i) that changing the other components of the formula or their amounts would yield the same results.
Kang et al. (https//bioprocessintl.com/manufacturing/formulation/rapid-formulation-development-formonoclonal-antibodies/, April 2016) shows that antibody formulation is empirical, with each antibody having potentially different optimized conditions, from pH to buffer to surfactant to saccharide or polyol (esp. pp. 2-3/7). Wang et al. (Int’l J. Pharmaceutics, 568:118505, 24 pages, 2019, Table 1 and section 2.2.1, 2.3.3 and 2.3.4) teaches that protein stability in solution, including antibody stability, is influenced by factors including formulation, process, temperature and light, with formulation factors including pH, ionic strength, excipients and contaminants, which contribute to colloidal stability, chemical degradation, aggregation and/or fragmentation. Not only do different excipients and buffers affect protein stability, but their concentration also is a variable. So too is the concentration of the therapeutic protein in solution (section 2.3.5). As stated in section 3. “Art of protein formulation development: The sensitivity and unpredictability of protein stability requires significant efforts in finding an optimal formulation condition/composition to maximize stability for different manufacturing steps and longterm storage. This exploratory and experimental process is formulation development.”
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
At the most for claim 1, it reasonably appears that only a bispecific antibody construct which is a BiTE® and a formulation therewith consisting of 1 mg/mL of the bispecific antibody, 10 mM L-glutamic acid, 9% (w/v) sucrose and 0.01% (w/v) polysorbate 80, at a pH of 5.2, as the formulation comprises less than 5% of HMW aggregates of the bispecific antibody construct after one month at 40˚C, meets the written description provision of 35 U.S.C. § 112(a), but not the full breadth of the claims, i.e., other concentrations of the recited buffer, saccharide and surfactant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicant argues (p. 8 of REMARKS) that claim 1 has been amended “to incorporate the features of dependent claims 2, 3, 5, 7, 10-12 and 26 and track particular formulation conditions used in Example 6.” As a result, amended claim 1 tracks Formulation C of Example 6, which exhibits less than 5% of high molecule weight (HMW) aggretates of the bispecific construct after one month’s storage at 40C. Applicant points to written description support in paragraph [00159] of the specification wherein: “[00159] Formulation C: 1 mg/mL BiTE® molecule, 10 mM L-glutamic acid, 9% (w/v) sucrose, 0.01% (w/v) Polysorbate 80, pH 5.2;” as well as Tables 5 and 6 for supporting results. The argument has been fully considered but is not persuasive. As pointed out by Applicant, the results are based on a single formulation: 1 mg/mL BiTE® molecule, 10 mM L-glutamic acid, 9% (w/v) sucrose, 0.01% (w/v) Polysorbate 80, pH 5.2. Claim 1 only partially limits the formulation, designating about 1 mg/mL of the bispecific antibody, which has the same format as a BiTE®, a pH of 5.2 and the presence of sucrose, polysorbate 80 and glutamate buffer, without amounts for any of these three critical ingredients. As discussed in the rejection, because the formulation is limited to comprising less than 5% HMW of the bispecific antibody construct after one month’s storage at 40˚C, and the specification discloses only one formulation at pH 5.2 meeting the limitation for % HMW after specific storage, the amounts of the sucrose, polysorbate 80 and glutamate buffer are important and the specification supports only the formulation comprising 10 mM L-glutamic acid, 9% (w/v) sucrose, 0.01% (w/v) Polysorbate 80. Neither independent claim 1 nor any dependent claim limits the amount of these three formulation ingredients.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 13-21 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-12, 18, 21, 22, 24 and 26 of copending Application No. 18/022,685 (‘685, reference application) for the reasons set forth in the previous Office action and recast here addressing the amendment and for the following reasons addressing the amendment to the instant claims: As the instant claims have been amended, the pH is 5.2, which falls within the range of about 4 to 7 set forth in claim 1 of ‘685. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each), comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1) or about 4 to about 7, including 4.2 (claims 1-6 and 8-11 of ‘685), which pHs overlap in view of the definition in the instant specification of “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]) Both claim wherein a binding domain is binds CD3 and construct is a single chain construct which also comprises a third domain of hinge-CH2-CH3-linker-hinge-CH2-CH3 (claims 21, 22, 24 of ‘685, and instant claims 1 and 13-15). The bispecific antibody in claim 1 of both applications is a fusion protein comprising two single chain variable fragments (scFvs) joined by a linker. The antibody construct is in a concentration of 1-20 mg/ml (claim 12 of ‘685 and instant claim 1). The bispecific antibody construct sequences in instant claim 21 and claim 26 of ‘685 are the same and comprise the VH and VL and CDRs thereof of CD3- and DLL3-binding scFvs (SEQ ID NO:76). The concentration of high molecule weight (HMW) aggregates is inherent to the formulation and storage conditions (instant claim 1). Note that the instant formulation “comprises” the listed ingredients and so may have more than those, e.g.¸ may have methionine. A two-way analysis of obviousness-type double patenting is not necessary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant requests (p. 10 or REMARKS) the rejection be held in abeyance until all other issues in this application are resolved since the copending application has a later patent term filing date than the instant application. The argument has been fully considered but is not persuasive. The rejection is not the only remaining rejection and cannot be held in abeyance. As a result, the rejection is maintained.
Conclusion
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 Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice .
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
September 4, 2026
Prosecution Insights