CTNF 18/574,161 CTNF 101658 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 12-151 AIA 26-51 12-51 Status of Claims Claims 1-7, 9, 10, 12, 14, 15, 17-19, 23, 27-29, 31, and 33 are pending and under examination. Priority This application is a 371 of PCT/US22/35533, filed 06/29/2022. This application claims the benefit of U.S. Provisional Application No. 63/216,616, filed 06/30/2021. Information Disclosure Statement The information disclosure statements (IDS) filed on 03/12/2024 and 04/09/2026 comply with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement are being considered by the examiner. Claim Objections 07-29-01 AIA Claim 1 is objected to because of the following informalities: insufficient preamble language. Instant claim recites “A method comprising” which does not provide context to the claim construction. For e.g. the preamble could read as “A method of polypeptide administration” or as relevant to the instant claims. "A claim preamble has the import that the claim as a whole suggests for it." Bell Communications Research, Inc. v. Vitalink Communications Corp., 55 F.3d 615, 620, 34 USPQ2d 1816, 1820 (Fed. Cir. 1995). See MPEP § 2112.02 . Appropriate correction is required. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-21-aia AIA Claim s 1-7, 9, 10, 12, 14, 15, 17-19, 23, 27-29, 31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018204907 (published November 8, 2018, cited in the IDS filed 03/12/2024) . WO’907 provides an improved pharmaceutical composition for storage and administration comprising a bispecific antibody construct, wherein the bispecific antibody construct is present at a concentration in the range; a preservative at a concentration effective to inhibit the growth of microbes; and a diluent wherein bispecific antibody construct is stable and recoverable (see Abstract). Regarding claim 1 : WO’907 discloses a method of preparing the pharmaceutical composition, wherein the bispecific antibody construct is provided as a lyophilisate, the lyophilisate preferably comprising a lyoprotector, a buffer and/or a surfactant, and wherein the lyophilisate is reconstituted by a diluent, comprising a preservative and preferably comprising a buffer and/or an excipient (see claim 29) WO’907 discloses saccharide and a surfactant pharmaceutical composition comprising one or more excipients selected from the group consisting of sucrose, trehalose, mannitol, sorbitol, arginine, lysine, polysorbate 20, polysorbate 80, poloxamer 188 (see claim 12). WO’907 discloses buffer system comprising a salt selected from the group consisting of phosphate, acetate, citrate, succinate and tartrate (see claim 6). WO’907 discloses diluent selected from benzyl alcohol, chlorobutanol, meta-cresol (see claim 1(ii)). WO’907 discloses the polypeptide is bispecific antibody construct (see claim 3). The teaching of WO’907 differ from that of the instantly claimed invention in that US’907 does not specifically state administering the reconstituted formulation to a subject in need within 12 hours of reconstitution. However, WO’907 does discloses the reconstituted formulation is administered intravenously continuously for 1 to 24 hours, preferably 1 to 10 or 2 to 5 hours (see claim 32). WO’907 discloses the pharmaceutical composition is stored until use as solution, as solution in frozen state or as lyophilisate, and is then administered, optionally after dilution or reconstitution (see claim 28). Also, WO’907 teaches the bispecific antibody construct is provided as a lyophilisate, the lyophilisate preferably comprising a lyoprotector, a buffer and/or a surfactant, and wherein the lyophilisate is reconstituted by a diluent, comprising a preservative and preferably comprising a buffer and/or an excipient (see [39]). WO’907 further discloses once the pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration (see [277]). WO’907 teaches the lyophilized material is first reconstituted in an appropriate liquid prior to administration (see [301]). WO’907 furthers explains the kit may additionally contain directions for use (e.g. in the form of a leaflet or instruction manual), means for administering the antibody construct of the present invention such as a syringe, pump, infuser or the like, means for reconstituting the antibody construct of the invention and/or means for diluting the antibody construct of the invention (see [313]). Based on the teachings of WO’907 above, it would have been obvious to optimize the time period within which the reconstituted formulation could be administered. It would have been obvious to adjust the time of pharmaceutical composition administration to be within 12 hours of reconstitution because the claimed time range overlaps with and within the range disclosed by WO’907, i.e., preferably continuously, for 1 to 24 hours, preferably 1 to 10 or 2 to 5 hours (see [43]). Prior art range fully overlaps and is broader than claimed range. Therefore, before the effective filing date of the claimed invention, the claimed invention was prima facie obvious to the artisan of ordinary skill. It would have been prima facie obvious for one of ordinary skill in the art to modify the teachings of US’907 with the expectation to achieve optimally stable pharmaceutical composition suitable for administration. See MPEP § 2144.05. Regarding claim 2 : WO’907 discloses commonly used preservatives include benzyl alcohol, phenol and m-cresol (see [5]). WO’907 further specifies that suitable formulation materials may include, but are not limited to: amino acids such phenylalanine (see [259]). The instant specification states, the diluents used for reconstitution included sterile water for injection, comprising 0.9% benzyl alcohol, 0.9% saline, saline comprising 0.9% benzyl alcohol, phenylalanine in purified water, phenol in purified water, and m-Cresol in purified water (see [0122]). Regarding claim 3 : WO’907 discloses the pH of the composition is in the range of 4.0 to 8.0, preferably in the range of pH 4.0 to 5.0 or 6.0 to 7.5 (see claim 11). Regarding claim 4 : WO’907 discloses pharmaceutical composition has a pH in the range of pH 4.0 to 6.5, preferably 4.2 to 4.8 (see [71]). Regarding claim 5 : WO’907 discloses the bispecific antibody construct is present in a concentration in the range of 1.0 to 20 mg/ml (see [16]). Regarding claim 7 : WO’907 discloses the composition comprises a buffer, which may be selected from the group consisting of potassium phosphate, acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, tartaric acid/sodium tartrate, histidine/histidine HCI, glycine, Tris, glutamate, acetate and mixtures thereof, and in particular from potassium phosphate, citric acid/sodium citrate, succinic acid, histidine, glutamate, acetate and combinations thereof (see [315]). Regarding claim 9 : WO’907 discloses buffer concentrations in the pharmaceutical composition specifically range from about 5 to about 200 mM (see [316]). Regarding claim 10 : WO’907 discloses buffer concentrations in the pharmaceutical composition preferably from about 10 to about 50 mM (see [316]). WO’907 further specifies the lyophilized material may be reconstituted in the same formulation the protein had been in prior to lyophilization (see [301]). Regarding claim 12 : WO’907 discloses composition comprising monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); carbohydrates may be non-reducing sugars, preferably trehalose, sucrose, octasulfate, sorbitol or xylitol (see [259]); sugars and sugar alcohols, such as trehalose, sucrose, octasulfate, mannitol, sorbitol or xylitol stachyose, mannose, sorbose, xylose, ribose, myoinisitose, galactose, lactitol, ribitol, myoinisitol, galactitol, glycerol, cyclitols (e.g., inositol) (see [259]); reducing sugars such as glucose and lactose (see [271]). Regarding claim 14 : WO’907 discloses sucrose may be present in the pharmaceutical composition in a concentration between 2% (w/v) and 12% (w/v), i.e. in a concentration of 12% (w/v), 1 1 % (w/v), 10% (w/v), 9% (w/v), 8% (w/v), 7% (w/v), 6% (w/v),. 5% (w/v), 4% (w/v), 3% (w/v) or 2% (w/v) (see [328]). WO’907 specifically gives example of blinatumomab DP formulation that contains 15% (w/v) trehalose dehydrate (see [367]). Regarding claim 15 : WO’907 discloses the antibody construct of the formulations further comprise surfactants (see [272]). WO’907 specifies surfactants include polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan polyethoxylates, and poloxamer 188 (see [272]). In certain embodiments, the pharmaceutical composition may contain formulation materials surfactants or wetting agents such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, … or a polyether… non-limiting examples for preferred detergents are Tween 20, Tween 40, Tween 60, Tween 80 and Tween 85; non-limiting examples for preferred polyethers are PEG 3350, and PEG 5000 (see 259]). Regarding claim 17 : WO’907 discloses that surfactant polysorbate 80 may be present in the pharmaceutical composition in a concentration between 0.001 % (w/v) and 0.5% (w/v), i.e. in a concentration of 0.5 % (w/v), 0.2% (w/v), 0.1 % (w/v), 0.08% (w/v), 0.05% (w/v), 0.02 % (w/v), 0.01 % (w/v), 0.008% (w/v), 0.005% (w/v), 0.002 % (w/v) or 0.001 % (w/v) (see [329]). Regarding claim 19 : WO’907 discloses the benzyl alcohol concentration of 0.9% (see Example 2, [357]). Regarding claim 23 : WO’907 discloses the pharmaceutical composition according to claim 1 , which is administered intravenously continuously for 1 to 24 hours, preferably 1 to 10 or 2 to 5 hours (see claim 32). Regarding claim 27 : WO’907 discloses the antibody constructs of the are particularly beneficial for highly weakened or even multimorbide cancer patients (see [128]). It is also envisaged that the antibody construct of the present invention is applied in a co-therapy, i.e., in combination with another anti-cancer medicament (see [261]). Regarding claim 28 : WO’907 discloses pharmaceutical composition is provided, comprising a bispecific antibody construct, binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain (see [12]). WO’907 claims the pharmaceutical composition, wherein the first binding domain of the bispecific antibody construct binds to at least one target cell surface antigen selected from the group consisting of CD19, CD33, EGFRvlll, MSLN, CDH19, FLT3, DLL3, CDH3,….(see claim 15). WO’907 specifies bispecific antibody construct as exemplified with DLL3xCD3 (see Figure 10, [55]). Regarding claim 29 : WO’907 discloses polypeptide sequences [see Table 5] and specifically sequences represented by the recited general formula below- Instant SEQ ID NO: 75 – same as SEQ ID NO: 102 Instant SEQ ID NO: 9 – same as SEQ ID NO: 26 Instant SEQ ID NO: 76 – same as SEQ ID NO: 103 Instant SEQ ID NO: 77 – same as SEQ ID NO: 104 Regarding claim 31 : WO’907 refers to any improvement of the disease state of a patient having a tumor or cancer or a metastatic cancer.. by the administration of an antibody construct according to the invention to a subject in need thereof. Such an improvement may also be seen as a slowing or stopping of the progression of the tumor or cancer or metastatic cancer of the patient (see [288]). WO’907 includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disease in question (see [289]). WO’907 specifies suitable host cells for the expression of glycosylated antibody construct of the invention are derived from multicellular organisms (see [247]), examples include human lung cells, human hepatoma line. Regarding claim 33 : WO’907 discloses polypeptide comprises the amino acid sequence (see Table 5). For example, Instant SEQ ID NO: 20 is same as SEQ ID NO: 39, Instant SEQ ID NO: 21 is same as SEQ ID NO: 40, Instant SEQ ID NO: 22 is same as SEQ ID NO: 41, Instant SEQ ID NO: 23 is same as SEQ ID NO: 74, Instant SEQ ID NO: 33 is same as SEQ ID NO: 51, Instant SEQ ID NO: 43 is same as SEQ ID NO: 62, etc. As stated above for claim 1, WO’907 teaches polypeptides [see Table 5] and specifically sequences represented by SEQ ID NO: 26, 102, 103, and 104, which reads applicants’ bispecific antibody polypeptides represented by the recited general formula. Regarding claim 6 : WO’907 discloses the chain antibody construct is present in a concentration in the range from 0.5 mg/ml to 20 mg/ml, preferably 0.5 μg/ml to 10 or 5 mg/m (see [12]). WO’907 further specifies the bispecific antibody construct is present in a concentration in the range of 1.0 to 20 mg/ml, or 1.0 to 10 mg/ml, or 1.0 mg/ml to 5 mg/ml or 1.0 mg/ml to 4 mg/ml or 1.0 mg/ml to 3 mg/ml, or 1.0 mg/ml to 2 mg/ml or 1.0 mg/ml to 1 mg/ml or 1.5 to 5 mg/ml or 1.5 mg/ml to 4 mg/ml or 1.5 mg/ml to 3 mg/ml, or 1.5 mg/ml to 2 mg/ml or 1.5 mg/ml to 1 mg/ml or 1.5 to 200 mg/ml (see [16]). Difference is that WO’907 is silent on representing the exact concentration of peptides in the composition. It appears that applicants’ claimed concentration falls within the broad concentration ranges of WO’907. Also, the instant specification states that the reconstituted formulation comprises the polypeptide (i.e., the bispecific T cell engaging antigen binding polypeptide) in a concentration ranging from about 0.5 mg/ml to about 50 mg/ml (e.g., from about 1 mg/ml to about 20 mg/ml or about 15 mg/ml) (see [0051]). Even if, range does not completely overlap, still claims are obvious in light of established case law, see below: Generally, differences in concentrations of components of a formulation will not support the patentability of subject matter encompassed by the prior art. Such formulations are results-effective variables which can be optimized. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious. Therefore, claims are obvious over the teachings of WO’907. Regarding claim 18 : WO’907 discloses the pharmaceutical composition – sucrose may be present in the pharmaceutical composition in a concentration between 2% (w/v) and 12% (w/v), i.e., in a concentration of 12% (w/v), 1 1 % (w/v), 10% (w/v), 9% (w/v), 8% (w/v), 7% (w/v), 6% (w/v),. 5% (w/v), 4% (w/v), 3% (w/v) or 2% (w/v). Preferred sucrose concentrations range between 4 % (w/v) and 10% (w/v) and more preferably between 6 % (w/v) and 10% (w/v); Polysorbate 80 may be present in the pharmaceutical composition in a concentration between 0.001 % (w/v) and 0.5% (w/v), i.e. in a concentration of 0.5 % (w/v), 0.2% (w/v), 0.1 % (w/v), 0.08% (w/v), 0.05% (w/v), 0.02 % (w/v), 0.01 % (w/v), 0.008% (w/v), 0.005% (w/v), 0.002 % (w/v) or 0.001 % (w/v). Preferred Polysorbate 80 concentrations range between 0.002 % (w/v) and 0.5% (w/v), and preferably between 0.005 % (w/v) and 0.02% (w/v) (see [328]). WO’907 further specifies composition comprises a buffer, which may be selected from the group consisting of potassium phosphate, acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, tartaric acid/sodium tartrate, histidine/histidine HCI, glycine, Tris, glutamate , acetate and mixtures thereof, and in particular from potassium phosphate, citric acid/sodium citrate, succinic acid, histidine, glutamate, acetate and combinations thereof (see [315]). WO’907 further specifies suitable buffer concentrations encompass concentrations of about 200 mM or less, such as about 190, 180, 170, 160, 150, 140, 130, 120, 1 10, 100, 80, 70, 60, 50, 40, 30, 20, 10 or 5 mM. The skilled person will be readily able to adjust the buffer concentrations in order to provide for stability of the pharmaceutical composition as described herein. Envisaged buffer concentrations in the pharmaceutical composition of the invention specifically range from about 5 to about 200 mM, preferably from about 5 to about 100 mM, and more preferably from about 10 to about 50 mM (see [316]). Difference is that WO’907 is silent on representing the exact concentration of glutamate in the composition. WO’907 teaches that various buffers or other additives may be used, where the polypeptides are formulated as lyophilized powders, for subsequent use in solution. WO’907 teaches suitable buffer concentrations encompass concentrations of about ….20, 10, 5 mM (see [316]) and claimed glutamate is a species for buffers (see [315]). The applicants’ claimed concentration falls within the broad concentration ranges of WO’907. It would have been obvious to adjust the amount of glutamate before the effective filing date of the claimed invention to arrive at the pharmaceutical composition of the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the teachings of US’907 to effectively change the amount of glutamate to achieve the stable formulation for administering the reconstituted formulation of polypeptide i.e., bispecific antibody construct. Generally, differences in concentrations of components of a formulation will not support the patentability of subject matter encompassed by the prior art. Such formulations are results-effective variables which can be optimized. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious. WO’907 teaches the pharmaceutical composition wherein the pH of the composition is in the range of 4.0 to 8.0, preferably in the range of pH 4.0 to 5.0 or 6.0 to 7.5, preferably at pH 7.0 (see claim 11). WO’907 discloses pharmaceutical composition has a pH in the range of pH 4.0 to 6.5, preferably 4.2 to 4.8 (see [71]). The instant specification states “a pH from about pH 4 to about pH 6” could be but is not limited to pH 4, 4.2, 4.6, 5.1, 5.5 etc. (see [0009]). Thus, the pH range taught by WO’907 falls within the applicants’ specified range. Therefore, a skilled person in the art would determine suitable pH range for the peptides through a routine optimization, since it is one of the critical step to stabilize a peptide in a composition in addition to other excipients. Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e., applicants’ individual components in the composition and their use in cancer therapy, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art. The motivation to modify and combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited references and to make the instantly claimed bispecific antibody construct lyophilized formulation composition with a reasonable expectation of success. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM. 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. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at (571) 270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. 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. /KOYELI BANERJEE/Examiner, Art Unit 1658 /Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658 Application/Control Number: 18/574,161 Page 2 Art Unit: 1658 Application/Control Number: 18/574,161 Page 3 Art Unit: 1658 Application/Control Number: 18/574,161 Page 4 Art Unit: 1658 Application/Control Number: 18/574,161 Page 5 Art Unit: 1658 Application/Control Number: 18/574,161 Page 6 Art Unit: 1658 Application/Control Number: 18/574,161 Page 7 Art Unit: 1658 Application/Control Number: 18/574,161 Page 8 Art Unit: 1658 Application/Control Number: 18/574,161 Page 9 Art Unit: 1658 Application/Control Number: 18/574,161 Page 10 Art Unit: 1658 Application/Control Number: 18/574,161 Page 11 Art Unit: 1658 Application/Control Number: 18/574,161 Page 12 Art Unit: 1658 Application/Control Number: 18/574,161 Page 13 Art Unit: 1658 Application/Control Number: 18/574,161 Page 14 Art Unit: 1658 Application/Control Number: 18/574,161 Page 15 Art Unit: 1658 Application/Control Number: 18/574,161 Page 16 Art Unit: 1658
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