CTNF 18/194,542 CTNF 100109 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. Election/Restrictions 08-25-01 AIA Applicant’s election without traverse of Group I, claims 20-35 in the reply filed on 11/25/2025 is acknowledged. 08-06 Accordingly, claims 43, 45, 47-49, and 52-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/25/2025. Claim Objections 07-29-01 AIA Claim s 20 and 22 are objected to because of the following informalities: The term “(HPMCAS)” immediately following “a hydroxypropyl methylcellulose acetate succinate” should be deleted and the subsequent term “HPMCAS” should be replaced with hydroxypropyl methylcellulose acetate succinate. The use of the abbreviation HPMCAS creates confusion as it appears the claims are limited to HPMCAS-LF and HPMCAS-HF, not HPMCAS . Appropriate correction is required. 07-29-01 AIA Claim 32 is objected to because of the following informalities: The term “an” should be inserted before the phrase acidic microclimate . Appropriate correction is required. 07-29-01 AIA Claim 33 is objected to because of the following informalities: The term “a” should be inserted before the phrase lactic acid/glycolic acid polymer system . Appropriate correction is required. 07-29-01 AIA Claim 26 is objected to because of the following informalities: The claim recites duplicate elements resulting in ambiguity. The term “(Fab’)2 fragment” is recited in the group of antibody fragment selections and the claim repeats (Fab’)2 fragment as an additional option . Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 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. 07-34-01 Claim 29 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 29 recites the limitations “reduced aggregation” and “reduced chemical degradation.” However, the claim does not provide a basis for which to determine whether aggregation and chemical degradation is reduced. Thus, it is unclear what the reduction is in comparison to. 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. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA 1. Claim s 20-29 and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Lassner et al., (US 2009/0226530 A1, Sept. 10, 2009) (hereinafter Lassner) in view of Bristol et al., (Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation, Nov. 05, 2021) (hereinafter Bristol) and Shenoy et al., (US 2009/0093617 A1, April 09, 2009) (hereinafter Shenoy) as evidenced by Zhang et al., (WO 2020/151756 A1, July 30, 2020) (hereinafter Zhang) . Lassner discloses a method for preparing a protein or peptide powder that includes spray drying a solution including a protein or peptide (e.g., an antibody or antigen binding portion thereof), and at least one excipient (abstract). The solution can include at least about 40 mg/mL of the protein, peptide, antibody or antigen binding portion thereof or the solution can have a different concentration of the protein, peptide, antibody or antigen binding portion thereof. The method of preparation can include concentrating or further concentrating the solution by any known method ([0065]). The term excipient refers to an agent that may be added to a formulation to provide a desired consistency, e.g., altering the bulk properties, to improve stability, and/or to adjust osmolality. Examples of commonly used excipients include, but are not limited to surfactants and polymers ([0038]) and Tween (i.e., polysorbate) is a surfactant ([0099]). The antigen-binding portion of an antibody include a Fab fragment and may be recombinant ([0048]). Examples of different types of antibodies, or antigen-binding fragments thereof, that may be used in the invention include, but are not limited to, a chimeric antibody, a human antibody, a humanized antibody ([0108]). The powder is stable at ambient temperatures (i.e., 20-25° C) for at least three months and/or stable at 40° C. for at least three months ([0011]). Other suitable excipients include, but are not limited to histidine ([0137]). Suitable additives can be added to the compositions such as buffers ([0140]). The spray drying methods of the invention minimize process related degradation and increase protein stability at ambient temperatures (e.g., as compared to freeze dried compositions) ([0007]). The stability of the protein is determined according to the percentage of monomer protein in the solution, with a low percentage of degraded (e.g., fragmented) and/or aggregated protein. An aqueous composition of the invention may include no more than 5% aggregate and/or degraded protein (i.e., reduced aggregation) ([0044]). The protein is in an amorphous state after spray drying ([0186]). The spray dried antibodies may be used with a MELTREX melt extrusion process, since it could be possible that the monoclonal antibody (mAb) incorporated within the glassy excipients matrix exhibit a higher stability towards thermal unfolding/denaturation ([0143]). Powdered pharmaceutical compositions can be melt extruded, pressed or otherwise processed to form solid compositions. The powder can be coated with polymers such as PLGA (i.e., a polymer system that produces acidic microclimate) to form sustained release and/or delayed release pharmaceutical compositions. Additionally or alternatively compositions may be encapsulated or coated with, e.g., an enteric coating ([0141). The compositions may be used to any disorder for which the therapeutic protein, peptide, antibody, or antigen binding portion thereof, is appropriate for treating, such as cancer ([0145]). When samples of the composition comprising Afelimomab (i.e., a monoclonal antibody) were stored at 5° C. and 25° C. good stability over 3 months was shown and no clear variations were found (Δ aggregation is below 1%) ([0214]). Lassner differs from the instant claims insofar as not disclosing wherein the formulation comprises an HPMCAS comprising about 8% acetate and about 15% succinate (HPMCAS-LF) and an HPMCAS comprising about 12% acetate and about 7% succinate (HPMCAS-HF). However, Bristol teaches that polymers play an important role in amorphous solid dispersions (ASDs), enhancing stability in the solid state and maintaining supersaturation in aqueous solutions of intrinsically low-water-soluble drug candidates. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is widely used in ASDs due to its hydrophobic/hydrophilic balance and ionizability of the substituent functionalities (Abstract). In order to extend drug supersaturation and prevent precipitation, polymer excipients are incorporated to inhibit nucleation and/or crystal growth (Introduction, page 4299). HPMCAS contains a range of substituents along the cellulosic backbone such as methyl, hydroxyl, hydroxypropyl, acetate, and succinate functionalities, which contribute to desirable properties in the solid and solution states. In the solid state HPMCAS is unionized and has a rigid structure, due to the cellulosic backbone, with a high Tg even under harsh conditions (e.g., 40 °C/75% relative humidity), increasing the physical stability of ASDs (page 4300, first paragraph). For all three grades of HPMCAS (HF/MF/LF), the change in conformation from the random coil to aggregate state significantly enhanced drug supersaturation and can inhibit crystal growth in supersaturated drug solution (Conclusions, page 4307). Lassner discloses pharmaceutical compositions of spray dried amorphous particle powders comprising excipients such as polymers (i.e., amorphous solid dispersions) that provide a desired consistency. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated HPMCAS-LF or HPMCAS-HF into the composition of Lassner since they are known and effective polymeric excipients used to significantly enhanced drug supersaturation (i.e., a desired consistency) in amorphous solid dispersions as taught by Bristol. As evidenced by Zhang, HPMCAS Type LF usually has 5.0-9.0% of acetyl group and 14.0-18.0% of succinoyl group; and Type HF usually has 10.0-14.0% of acetyl group and 4.0-8.0% of succinoyl group ([0064]). The combined teachings of Lassner and Bristol do not disclose wherein the composition comprises histidine present as histidine-HCl, polysorbate-20, or wherein the pH of the formulation is about 5.5 to about 7.0. However, Shenoy discloses crystals of whole antibodies and fragments thereof, and formulations and compositions comprising such crystals (abstract). The antibody fragment is a Fab antibody fragment (Claim 43) and is dried by spray drying (Claim 44). Preferred ingredients or excipients include salts of amino acids such as histidine and emulsifying agents like polysorbates ([0119]), specifically, polysorbate 20 ([0092]). Histidine is a buffering agent ([0086]). The excipient concentration is typically between about 0.01 and about 10% (w/w). The ingredient concentration is between about 0.01 and about 90% (w/w). The crystal concentration is between about 0.01 and about 99% (w/w) ([0191]). The formulations or compositions have a Fab antibody fragment concentration greater than about 10 mg/ml ([0175]). Example 31 discloses the use of 0.495 mg/ml L-histidine HCl and 1.8 mg polysorbate 20 ([0275]). Example 64 discloses a Rituximab (i.e., antibody) crystal slurry prepared in a buffer with Tween 80 (i.e., polysorbate) at a pH of 6.5 before being stored ([0378]). The antibodies may be encapsulated in PLGA ([0136]). Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. Lassner discloses wherein the composition comprises histidine and a buffer. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated L-histidine HCl into the composition of Lassner since it is a known and effective histidine salt and a buffer used for compositions comprising antibodies as taught by Shenoy. Lassner discloses wherein the composition comprises surfactants. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated polysorbate-20 into the composition of Lassner since it is a known and effective emulsifying agent (i.e., surfactant) used in compositions comprising antibodies as taught by Shenoy. Regarding the limitation of claims 20, 21, 22, and 23 reciting wherein the pH of the formulation is about 5.5 to about 7.0 and is about 6.5, as discussed above, Shenoy discloses compositions comprising antibodies prepared in a buffer with Tween 80 (i.e., a surfactant) at a pH of 6.5. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the composition of Lassner to have a pH of 6.5 since this is a known and effective pH for compositions comprising antibodies as taught by Shenoy. Regarding the limitation of claims 20-23 reciting a ratio of the HPMCAS-LF or HPMCAS-HF to antibody in the formulation is about 4:1 (mg/mg), about 1:1 (mg/mg), or about 1:4 (mg/mg), as discussed above, the composition of Lassner comprises at least about 40 mg/mL of an amorphous protein or peptide (e.g., an antibody or antigen binding portion thereof). Thus, one of ordinary skill in the art would have selected an amount of antibody as taught by Lassner. Bristol teaches that HPMCAS-LF and HPMCAS-HF are used to stabilize the amorphous composition. Thus, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at an amount of HPMCAS-LF and HPMCAS-HF depending on the amount necessary to stabilize the composition. After arriving at these amounts, a ratio between these two amounts is obtained. Therefore, since the ratio is based on desired effects, the claimed ratio would have been obvious based on the desired effects of these compounds. Where 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. See MPEP 144.05(II)(A). Regarding the limitation of claims 20-23 reciting a histidine-HCl buffer at a concentration of about 5 mM to about 20 mM and about 10 mM, as discussed above, the composition of Lassner comprises histidine and a buffer. Shenoy teaches that L-histidine HCl is a known and effective histidine salt used for buffering compositions comprising antibodies. Thus, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at an amount of L-histidine HCl depending on the desired pH of the composition. Where 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. See MPEP 144.05(II)(A). Regarding the limitation of claims 20-23 reciting polysorbate 20 at a concentration of about 0.005% (w/v) to about 0.5% (w/v) and about 0.01% (w/v), as discussed above, Shenoy teaches the use of polysorbate 20 as an emulsifying agent. Thus, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at an amount of polysorbate 20 necessary to emulsify the composition of Lassner. Where 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. See MPEP 144.05(II)(A). Regarding the limitation of claims 21 and 23 reciting a concentration of antibody of about 10 mg/mL, as discussed above, Lassner teaches that the composition can have a different concentration of the antibody or antibody fragment and that the compositions may be used to treat any disorder for which the therapeutic protein, peptide, antibody, or antigen binding portion thereof, is appropriate for treating. Accordingly, one of ordinary skill in the art would have arrived at the claimed concentration of antibody through routine experimentation depending on the amount of antibody necessary to effectively treat the disorder for which it is formulated to treat. Where 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. See MPEP 2144.05(II)(A) . 07-21-aia AIA 2. Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Lassner et al., (US 2009/0226530 A1, Sept. 10, 2009) (hereinafter Lassner) in view of Bristol et al., (Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation, Nov. 05, 2021) (hereinafter Bristol), Shenoy et al., (US 2009/0093617 A1, April 09, 2009) (hereinafter Shenoy) and further in view of Liu et al., (Characterization of the acidic species of a monoclonal antibody using free flow electrophoresis fractionation and mass spectrometry, Feb. 27, 2020) (hereinafter Liu) . The teachings of Lassner, Bristol, and Shenoy are discussed above. Lassner, Bristol, and Shenoy do not teach wherein the reduced chemical degradation comprises reduced formation of succinimide variants of the antibody and/or reduced formation of pyroglutamate variants of the antibody. However, Liu teaches that heterogeneity of recombinant monoclonal antibodies can be caused by a variety pathways, including cell culture conditions, downstream purification, formulation processing, and storage. These product variants may negatively impact the efficacy, safety and limit the half-life. Therefore, it is critical to routinely monitor the purified antibody variants to ensure product integrity, lot to lot consistency, and stability. Charge heterogeneity analysis is one of the most important aspects in the characterization of monoclonal antibodies. The charge species with lower isoelectric points (pIs) compared with that of the main species are defined as acidic variants. Succinimide formation has been identified to contribute to antibody acidic variant formation. Monitoring of charge variants is needed throughout the product development process to ensure product and process consistency (Introduction, page 1). As discussed above, Lassner teaches that the composition comprises antibodies that may be monoclonal and recombinant. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have formulated the composition of Lassner to have a reduced formation of succinimide variants of the antibody since succinimide formation leads to antibody acidic variant formation and product variants may negatively impact the efficacy, safety and limit the half-life of recombinant monoclonal antibodies as taught by Liu . 07-21-aia AIA 3. Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Lassner et al., (US 2009/0226530 A1, Sept. 10, 2009) (hereinafter Lassner) in view of Bristol et al., (Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation, Nov. 05, 2021) (hereinafter Bristol), Shenoy et al., (US 2009/0093617 A1, April 09, 2009) (hereinafter Shenoy), and further in view of Thackaberry et al., (Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response, August, 2017) (hereinafter Thackaberry) . The teachings of Lassner, Bristol, and Shenoy are discussed above. Lassner, Bristol, and Shenoy do not teach wherein the antibody is encapsulated in a PLGA rod. However, Thackaberry teaches that Poly(lactic-co-glycolic) acid (PLGA) inserts have been successfully developed for the treatment of posterior eye disease as a means of reducing injection frequency of intravitreally administered therapeutics (Purpose). Poly(lactic-co-glycolic) acid (PLGA) is a commonly used bioerodible polymer used extensively in sustained release delivery systems and can be formulated as microspheres or rods (page 4274, first paragraph). PLGA microspheres were prepared using a continuous double emulsion, solvent-extraction microencapsulation process (page 4275, Materials and Methods) and were assessed in vitro with PLGA rods (page 4277, In Vitro Studies). However, an inflammatory response to PLGA microspheres was noted to be driven by their size, shape, and/or surface area rather than the chemical characteristics of the polymer (page 4283, last paragraph). Intravitreally administered PLGA microspheres with average diameters between 20 and 100 lm produce ocular inflammation, and a localized, progressive foreign body response in rabbits and NHPs. By contrast, PLGA rods were well tolerated in rabbits, suggesting that the size, shape, and/or surface area of the PLGA depots are critical attributes in determining toxicity (page 4284, last paragraph). Lassner discloses powdered pharmaceutical compositions coated with PLGA to form sustained release pharmaceutical compositions. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have encapsulated the pharmaceutical composition of Lassner in a PLGA rod since the size, shape, and/or surface area of the PLGA depots are critical attributes in determining toxicity and PLGA rods are well tolerated shapes of sustained delivery pharmaceutical compositions as taught by Thackaberry. Conclusion Claims 20-35 are rejected. Claims 43, 45, 47-49, and 52-53 are withdrawn. No claims are allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Samantha J Knight whose telephone number is (571)270-3760. The examiner can normally be reached Monday - Friday 8:30 am to 5:00 pm ET. 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, Ali Soroush can be reached at (571)272-9925. 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. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /S.J.K./Examiner, Art Unit 1614 /TRACY LIU/Primary Examiner, Art Unit 1614 Application/Control Number: 18/194,542 Page 2 Art Unit: 1614 Application/Control Number: 18/194,542 Page 3 Art Unit: 1614 Application/Control Number: 18/194,542 Page 4 Art Unit: 1614 Application/Control Number: 18/194,542 Page 5 Art Unit: 1614 Application/Control Number: 18/194,542 Page 6 Art Unit: 1614 Application/Control Number: 18/194,542 Page 7 Art Unit: 1614 Application/Control Number: 18/194,542 Page 8 Art Unit: 1614 Application/Control Number: 18/194,542 Page 9 Art Unit: 1614 Application/Control Number: 18/194,542 Page 10 Art Unit: 1614 Application/Control Number: 18/194,542 Page 11 Art Unit: 1614 Application/Control Number: 18/194,542 Page 12 Art Unit: 1614 Application/Control Number: 18/194,542 Page 13 Art Unit: 1614 Application/Control Number: 18/194,542 Page 14 Art Unit: 1614