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
Claims 1-10, 12-13, and 15-17 are pending in the instant application.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C.
119(a)-(d) prior to declaration of an interference, a certified English translation of the
foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/CN2022/107134 filed on 7/21/2022 in the absence of a certified translation of
CN202110823295.2 filed on 7/21/2021.
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 1-10, 12-13, and 15-17 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.
Regarding claims 1-10, 12-13, and 15-17, the claims list a genus followed by the term “such as” “preferably” or “for example” then describes species of the genus. It is not clear whether the recitation of imaging flow cytometry is a preferred example—and therefore not limiting—or further limitations of the scope of the claim.
The genus with optional species described are:
claim 1) n is 1-10, preferably 1-8; pH of about 5.0 to 6.5, preferably a pH about 5.5 to about 6.5, more preferably a pH of about 5.9 to about 6.2;
claim 2) concentration of about 10 mM to about 50 mM, preferably about 20 mM to about 40 mM, and more preferably about 30 mM;
claim 3) surfactant is preferably a polysorbate, more preferably polysorbate 80 or polysorbate 20, and most preferably polysorbate 80;
claim 4) concentration of about 0.01 mg/mL to about 1.0 mg/mL, preferably about 0.1 mg/mL to about 0.3 mg/mL, and more preferably about 0.2 mg/mL;
claim 5) saccharide is preferably selected from the group consisting of sucrose and trehalose dihydrate and is most preferably sucrose;
claim 6) concentration of about 25 mg/mL to about 80 mg/mL, preferably about 30 mg/mL to about 50 mg/mL, and more preferably about 40 mg/mL;
claim 7) amino acid or an amino acid salt, and the amino acid or the amino acid salt is preferably selected from the group consisting of glycine and arginine hydrochloride and is more preferably glycine;
claim 8) concentration of about 6 mg/mL to about 15 mg/mL, preferably about 7 mg/mL to about 11 mg/mL, and more preferably about 9 mg/mL;
claim 10) pharmaceutical composition…wherein preferably, the pharmaceutical composition comprises the following components: (a)…;
claim 17) cancer is preferably head and neck… ; more preferably, the lymphoma is selected from…
Claims 9, 12-13, and 15-16 are dependent on claim 1 and further contain the indefinite subject matter.
Claim Rejections – 35 USC § 112(a)
Claims 1-10, 12-13, and 15-17 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.
Regarding instant claim 1, the structure includes a maleimide bonded to an antibody, which indicates conjugation to a cysteine residue in the antibody. Cysteine drug conjugates produced via partial reduction of interchain disulfide bonds generate up to eight reactive cysteine thiol groups, thus, only n values 1-8 are available for conjugation. Claims 2-10, 12-13, and 15-17 are dependent on claim 1 without narrowing the structure to an n of 1-8 and are also rejected; and
Regarding instant claim 17, a method of treating cancer is claimed wherein the treatment comprises administering a pharmaceutical composition that comprises a TROP2 targeted ADC, but the method does not require the cancer to express the TROP2 target. The TROP2 antibody drug conjugate requires the cancer cells express TROP2 for cancer cell targeting.
Scope of the claimed genus
Regarding instant claim 1, a pharmaceutical composition is claimed comprising an antibody drug conjugate wherein the antibody drug conjugate has the structure:
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wherein n is 1-10. Claims 2-10, 12-13, and 15-17 are dependent on claim 1 without narrowing the structure to an n of 1-8 and are also rejected; and
Regarding instant claim 17, a method of treating cancer is claimed wherein the treatment comprises administering the pharmaceutical composition above that comprises a TROP2 targeted ADC, but the method does not require the cancer to express the TROP2 target.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification teaches preparation of antibody drug conjugates with the structure
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wherein n is about 4 (instant specification, page 23, [0106]). ADC-1 was effective at killing TROP-2 expressing cancer cells in cell-based assays (specification, page 33, Tables 6-7) and in vivo, in a method of treatment of cancer cells expressing TROP-2, wherein a pharmaceutical composition comprising a pharmaceutical excipient and ADC-1 was administered to a subject in need thereof (specification, pages 35-36, Tables 8-9). The instant specification does not teach an effective pharmaceutical composition comprising an ADC with the structure
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, wherein 1) the n of the ADC is greater than 8; or 2) the cancer does not express TROP-2.
State of the Relevant Art
The prior art has taught most ADCs are synthesized by conjugating a cytotoxic compound or “payload” to a monoclonal antibody (Behrens CR et al. (Mol. Pharmaceutics 2015, 12, 11, 3986–3998), page 3986, left column, first paragraph). Behrens taught the payloads are conjugated using amino or sulfhydryl specific linkers that react selectively with lysines or cysteines on the antibody surface, wherein a typical antibody contains over 50 lysines and eight interchain cysteines as potential conjugation sites (page 3986, left column, first paragraph). Behrens taught conjugation through antibody cysteines minimizes ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites (page 3986, right column, first paragraph). The process typically involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive cysteine thiol groups, followed by conjugation of payloads containing thiol-specific maleimide linkers (page 3986, right column, first paragraph). Behrens taught ADCs with suboptimal DARs are prone to aggregation, poor solubility, and instability, which often lead to increased toxicity and/or inadequate efficacy in vivo (page 3986, left column, first paragraph). Behrens taught the discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of linkers that lack site-specificity, results in heterogeneous ADCs that vary in both DAR and the conjugation sites (page 3986, left to right column bridging sentence). Behrens taught consequently, most of the ADCs in clinical development for cancer indications contain dozens or more of chemically distinct ADC molecules, each with unique pharmacological properties (page 3986, right column, first paragraph);
The prior art has taught anti-TROP2 ADCs that target TROP2 on cancer cells. Zaman S et al. Targeting Trop-2 in solid tumors: future prospects (Onco Targets Ther. 2019 Mar 1; 12:1781–1790.) taught DS-1062 markedly reduced in vitro cancer cell growth with IC50 dosing in the nanomolar range in Trop-2+ cell lines (CFPAC1, BxPC-3); to contrast the group also demonstrated that in Trop-2-negative tumor cells (Calu-6), 100-fold greater dosing was needed to achieve IC50 (page 1787, left to right column bridging paragraph). Thus, cancer cells that do not express TROP2 have diminished targeting of cancer cells that do not express TROP2. Further, targeting cancer cells that do not express TROP2 would result in unpredictable efficacy in comparison to side effects on normal cells.
Claims 1-10, 12-13, and 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: 1) an ADC with an n of 1-8; and 2) a method of treating a TROP2 positive cancer, does not reasonably provide enablement for: 1) an ADC with an n of more than 8; and 2) a method of treating a non-TROP2 positive cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding instant claim 1, the structure includes a maleimide bonded to an antibody, which indicates conjugation to a cysteine residue in the antibody. Cysteine drug conjugates produced via partial reduction of interchain disulfide bonds generate up to eight reactive cysteine thiol groups, thus, only n values 1-8 are available for conjugation. Claims 2-10, 12-13, and 15-17 are dependent on claim 1 without narrowing the structure to an n of 1-8 and are also rejected; and
Regarding instant claim 17, a method of treating cancer is claimed wherein the treatment comprises administering a pharmaceutical composition that comprises a TROP2 targeted ADC, but the method does not require the cancer to express the TROP2 target. The TROP2 antibody drug conjugate requires the cancer cells express TROP2 for cancer cell targeting.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Regarding instant claim 1, a pharmaceutical composition is claimed comprising an antibody drug conjugate wherein the antibody drug conjugate has the structure:
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wherein n is 1-10. Claims 2-10, 12-13, and 15-17 are dependent on claim 1 without narrowing the structure to an n of 1-8 and are also rejected; and
Regarding instant claim 17, a method of treating cancer is claimed wherein the treatment comprises administering the pharmaceutical composition above that comprises a TROP2 targeted ADC, but the method does not require the cancer to express the TROP2 target.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification teaches preparation of antibody drug conjugates with the structure
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wherein n is about 4 (instant specification, page 23, [0106]). ADC-1 was effective at killing TROP-2 expressing cancer cells in cell-based assays (specification, page 33, Tables 6-7) and in vivo, in a method of treatment of cancer cells expressing TROP-2, wherein a pharmaceutical composition comprising a pharmaceutical excipient and ADC-1 was administered to a subject in need thereof (specification, pages 35-36, Tables 8-9). The instant specification does not teach an effective pharmaceutical composition comprising an ADC with the structure
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, wherein 1) the n of the ADC is greater than 8; or 2) the cancer does not express TROP-2.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The prior art has taught most ADCs are synthesized by conjugating a cytotoxic compound or “payload” to a monoclonal antibody (Behrens CR et al. (Mol. Pharmaceutics 2015, 12, 11, 3986–3998), page 3986, left column, first paragraph). Behrens taught the payloads are conjugated using amino or sulfhydryl specific linkers that react selectively with lysines or cysteines on the antibody surface, wherein a typical antibody contains over 50 lysines and eight interchain cysteines as potential conjugation sites (page 3986, left column, first paragraph). Behrens taught conjugation through antibody cysteines minimizes ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites (page 3986, right column, first paragraph). The process typically involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive cysteine thiol groups, followed by conjugation of payloads containing thiol-specific maleimide linkers (page 3986, right column, first paragraph). Behrens taught ADCs with suboptimal DARs are prone to aggregation, poor solubility, and instability, which often lead to increased toxicity and/or inadequate efficacy in vivo (page 3986, left column, first paragraph). Behrens taught the discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of linkers that lack site-specificity, results in heterogeneous ADCs that vary in both DAR and the conjugation sites (page 3986, left to right column bridging sentence). Behrens taught consequently, most of the ADCs in clinical development for cancer indications contain dozens or more of chemically distinct ADC molecules, each with unique pharmacological properties (page 3986, right column, first paragraph);
The prior art has taught anti-TROP2 ADCs that target TROP2 on cancer cells. Zaman S et al. Targeting Trop-2 in solid tumors: future prospects (Onco Targets Ther. 2019 Mar 1;12:1781–1790.) taught DS-1062 markedly reduced in vitro cancer cell growth with IC50 dosing in the nanomolar range in Trop-2+ cell lines (CFPAC1, BxPC-3); to contrast the group also demonstrated that in Trop-2-negative tumor cells (Calu-6), 100-fold greater dosing was needed to achieve IC50 (page 1787, left to right column bridging paragraph). Thus, cancer cells that do not express TROP2 have diminished targeting of cancer cells that do not express TROP2. Further, targeting cancer cells that do not express TROP2 would result in unpredictable efficacy in comparison to side effects on normal cells.
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 1-10, 12-13, and 15-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 7-8, 12-14, 16, 18-20, 22-27, 29, 31, 33-39, of copending Application No. 17/793,005 in view of Strickly RG et al. (Journal of Pharmaceutical Sciences 110 (2021) 2590−2608), Kang J et al. Rapid Formulation Development for Monoclonal Antibodies (BioProcess International 2016 14(4) 40-45), and US 2018/0142032 (Baudat Y et al.), and WO 2017/136433 (Gutka H et al. ).
‘005 taught anti-TROP2 antibody-drug conjugates (ADCs) and methods of treating cancer with the ADCs, wherein the structure comprises
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wherein Y is -O-(CRaRb)m-CR1R2-C(O)-; Ra and Rb are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen and C1.6 alkyl; R1 is C1.6 haloalkyl or C3_ cycloalkyl; R2is selected from the group consisting of hydrogen, C1.6 haloalkyl and C3-6 cycloalkyl; or, R1 and R2, together with carbon atoms connected thereto, form C3-6 cycloalkyl; mis 0 or 1; n is a decimal or an integer from 1 to 10; L is a linker unit; and Pc is an anti-TROP-2 antibody or an antigen-binding fragment thereof; wherein the anti-TROP-2 antibody or the antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an a HCDR1, an a HCDR2 and an a HCDR3 set forth in SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, respectively, and the light chain variable region comprises an a LCDR1, an a LCDR2 and an a LCDR3 set forth in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively in claims 1, 4-5, 7-8, 12-14, 16, 18-20, 22-27, 29, 31, 33-39.
‘005 taught an anti-TROP2 antibody-drug conjugates (ADCs) with the structure above in copending claim 1 with an n of 1-8, wherein the anti-TROP2 antibody comprises a heavy chain of ‘005 SEQ ID NO:13 and a light chain of ‘005 SEQ ID NO:14 in copending claim 8, wherein the structure is:
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in copending claims 18-19. ‘005 taught a method of treating a cancer in a subject in need thereof comprising administering to the subject an anti-TROP2 antibody-drug conjugates (ADCs) with the structure above in copending claim 1, wherein the cancer is breast cancer in copending claim 31.
‘005 does not teach the formulation details of the pharmaceutical composition, but this is obvious in view of Strickly, Kang, Baudat, and Gutka
Strickly taught a typical lyophilized antibody formulation comprises 10 mg/ml antibody, 10 mM histidine, 50 mg/ml sucrose, 0.2 mg/ml polysorbate 80 at pH 6 in a single dose vial (page 2605, Table 7). Strickly taught histidine as a buffer and the concentration is typically less than 50 mM (page 2592, right column, first sentence). Strickly taught excipients to adjust tonicity or osmolality, and lyoprotectants in commercially available antibody formulations, wherein sucrose is 25-100 mg/ml (page 2598, Table 2). Strickly taught polysorbate 80 is the most common surfactant and most commonly used at 0.2 mg/ml (page 2603, Table 5). Strickly taught glycine is used in a range from 0.1 to 80 mg/ml (page 2600, left column, Glycine). Strickly taught antibody concentrations for intravenous formulations typically range from 10-50 mg/ml (page 2598, right column, first paragraph). Strickly taught 9/10 approved antibody drug conjugates are formulated as lyophilized powders (page 2593, right column, last two paragraphs).
Kang taught by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang taught although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang taught lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang taught 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang taught Table 1 lists excipients used in these antibody formulations. Kang taught some commonalities can be observed: histidine is present in 35% of formulations (page 40, middle column, second bullet), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), and 80% of formulations used one of three surfactants that includes polysorbate 80 (page 40, middle column, third bullet). Kang taught glycine is used in about 20% of antibody formulations (page 40, right column, third bullet). Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in-depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang taught the stage two screening study can test the excipients sucrose, polysorbate 80, and glycine in a screening design of experiment (DoE) study (page 42, middle to left column bridging paragraph). Kang taught histidine has a pKa value of 6 (page 42, middle column, second to last paragraph). Kang taught in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
Baudat taught a drug formulation of 5.7 mg/ml DM4-SPDB-chMAb1 in HGS buffer (page 54, [0853-0854]), wherein the HGS buffer comprises 10 mM histidine, 130 mM glycine, 5% (w/v) sucrose, 0.01% Tween 80 at pH 5.5 (page 53, [0845]). Baudat taught DM4-SPDB-chMAb1 in was effective in vivo (Fig. 5-6). Baudat taught a method of preparation of sterile powders for the preparation of sterile injectable solutions, wherein a preferred method of preparation is a freeze-drying technique which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, wherein freeze-drying is a method of lyophilization (page 26, [0458]).
Gutka taught a histidine buffer can be prepared by mixing histidine base and histidine hydrochloride as indicated in the table below
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(page 12, [0063]).
Regarding instant claims 1-10, 12-13, and 15-17, it would have been obvious for a person having ordinary skill in the art to modify ‘005 copending claims 1, 8, 18-19, and 31 of a method of treating breast cancer in a subject in need thereof comprising administering to the subject an anti-TROP2 ADC, wherein the structure is:
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with an n of 1-8, wherein the anti-TROP2 antibody comprises a heavy chain of ‘005 SEQ ID NO:13 and a light chain of ‘005 SEQ ID NO:14 – by:
Treating a subject with breast cancer that expressed TROP2;
Formulating the ADC in a pharmaceutical composition comprising a typical lyophilized antibody formulation of antibody, histidine, sucrose, polysorbate 80 at pH 6 in a single dose vial in view of Strickly;
Including glycine in the pharmaceutical composition formulation in view of Strickly, Kang and Baudat;
Using a concentration range of 10 – 50 mM of histidine, 25-100 mg/ml sucrose, 0.2 mg/ml polysorbate 80, and glycine is used in a range of 0.1 to 80 mg/ml in the pharmaceutical composition in view of Strickly and Kang;
Preparing a histidine-histidine-HCl buffer for the histidine buffer formulation in view of Gutka;
Preparing the lyophilized formulation with a method of freeze-drying which is lyophilization in view of Baudat.
This is obvious because:
1a) an anti-TROP2 ADC would effectively target cancer cells that expressed the antibody target TROP2;
2a) Strickly taught a typical lyophilized antibody pharmaceutical composition formulation comprises antibody, histidine, sucrose, polysorbate 80 at pH 6 in a single dose vial and 9/10 approved ADCs are lyophilized;
3a) Strickly taught glycine use in antibody formulation;
3b) Kang taught: i) glycine is used in about 20% of antibody pharmaceutical composition formulations; ii) formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients; iii) Kang taught the stage two screening study testing the excipients sucrose, polysorbate 80, and glycine in a screening design of experiment (DoE) study; and iv) in just a few weeks, researchers can develop a stable formulation for antibody product development.
3c) Baudat taught a drug pharmaceutical composition formulation of an ADC wherein DM4-SPDB-chMAb1 was in HGS buffer which comprised histidine, glycine, sucrose, Tween 80 (polysorbate 80) was effective;
4a) Strickly taught: i) antibody concentrations for intravenous pharmaceutical composition formulations typically range from 10-50 mg/ml; ii) histidine as a buffer ranging from 10 mM to less than 50 mM; iii) excipients to adjust tonicity or osmolality, and lyoprotectants in commercially available antibody formulations, wherein sucrose is 25-100 mg/ml ; iv) glycine is used in a range from 0.1 to 80 mg/ml; v) polysorbate 80 is the most common surfactant and most commonly used at 0.2 mg/ml; and vi) a pH of 6.0;
4b) Kang taught: i) by studying commercial antibody products, they established a rich database for successful antibody formulations; ii) although every antibody is unique, the molecules are highly similar structurally and lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations; iii) Table 1 lists excipients used in these antibody commercial formulations with commonalities wherein histidine is present in 35% of formulations, sucrose was present in 30% of liquid formulations, 80% of formulations used one of three surfactants that includes polysorbate 80, and glycine is used in about 20% of antibody formulations; iv) formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients; v) the stage two screening study tests the excipients sucrose, polysorbate 80, and glycine in a screening design of experiment (DoE) study; vi) histidine has a pKa value of 6; and vii) in just a few weeks, researchers can develop a stable formulation for antibody product development;
5a) Gutka taught a histidine buffer can be prepared by mixing histidine base and histidine hydrochloride as indicated in the table above. Thus, a person having ordinary skill in the art would obviously be able to prepare a histidine buffer with histidine and histidine HCl; and
6a) Baudat taught preparing sterile powders for the preparation of sterile injectable solutions, wherein the preferred method of preparation is a freeze-drying technique which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, wherein freeze-drying is a method of lyophilization.
There is a reasonable expectation of success because:
1a) an anti-TROP2 ADC would effectively target cancer cells that expressed the antibody target TROP2;
2a) Strickly taught a typical lyophilized antibody pharmaceutical composition formulation comprises antibody, histidine, sucrose, polysorbate 80 at pH 6 in a single dose vial and 9/10 approved ADCs are lyophilized;
3a) Strickly taught glycine use in antibody formulation;
3b) Kang taught: i) glycine is used in about 20% of antibody formulations; ii) formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients; iii) Kang taught the stage two screening study testing the excipients sucrose, polysorbate 80, and glycine in a screening design of experiment (DoE) study; and iv) in just a few weeks, researchers can develop a stable formulation for antibody product development;
3c) Baudat taught a drug formulation of an ADC wherein DM4-SPDB-chMAb1 was in HGS buffer which comprised histidine, glycine, sucrose, Tween 80 (polysorbate 80) was effective. Thus, these formulation components have been previously known to work effectively in an ADC;
4a) Strickly taught: i) antibody concentrations for intravenous formulations typically range from 10-50 mg/ml; ii) histidine as a buffer ranging from 10 mM to less than 50 mM; iii) excipients to adjust tonicity or osmolality, and lyoprotectants in commercially available antibody formulations, wherein sucrose is 25-100 mg/ml ; iv) glycine is used in a range from 0.1 to 80 mg/ml; v) polysorbate 80 is the most common surfactant and most commonly used at 0.2 mg/ml; and vi) a pH of 6.0;
4b) Kang taught: i) by studying commercial antibody products, they established a rich database for successful antibody formulations; ii) although every antibody is unique, the molecules are highly similar structurally and lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations; iii) Table 1 lists excipients used in these antibody commercial formulations with commonalities wherein histidine is present in 35% of formulations, sucrose was present in 30% of liquid formulations, 80% of formulations used one of three surfactants that includes polysorbate 80, and glycine is used in about 20% of antibody formulations; iv) formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients; v) the stage two screening study tests the excipients sucrose, polysorbate 80, and glycine in a screening design of experiment (DoE) study; vi) histidine has a pKa value of 6; and vii) in just a few weeks, researchers can develop a stable formulation for antibody product development;
5a) Gutka taught a histidine buffer can be prepared by mixing histidine base and histidine hydrochloride as indicated in the table above. Thus, a person having ordinary skill in the art would obviously be able to prepare a histidine buffer with histidine and histidine HCl; and
6a) Strickly taught effective lyophilization formulations and that 9/10 approved antibody drug conjugates are formulated as lyophilized powders, which would require a method of lyophilization.
This would produce a method of treating breast cancer expressing TROP2, which would also be a TROP2-mediated disease or condition (instant claims 16-17), in a subject in need thereof comprising administering to the subject an anti-TROP2 ADC in a pharmaceutical composition, wherein the structure is:
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with an n of 1-8, wherein the anti-TROP2 antibody comprises a heavy chain of ‘005 SEQ ID NO:13 and a light chain of ‘005 SEQ ID NO:14 , wherein the ADC is formulated as a lyophilized pharmaceutical composition formulation (instant claim 13) comprising: i) 10-50 mg/ml of the anti-TROP2 ADC above; ii) 10-50 mM histidine-histidine-HCl buffer; iii) 25-100 mg/ml sucrose, which is a saccharide; iv) 0.1-80 mg/ml glycine; v) 0.2 mg/ml polysorbate 80, which is a surfactant; and vi) a pH of 6.0 (instant claims 1-10), in a single dose vial, which is container for the ADC pharmaceutical composition article of manufacture (instant claim 15), wherein the lyophilized formulation is obtained by lyophilizing the pharmaceutical composition (instant claim 12).
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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