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 .
Claims 2, 3, 5, 7-12, 17, 20, 24-38, 40-42, 46, 47, 50-54 and 56-69 have been canceled. Claims 1, 4, 6, 13-16, 18, 19, 21-23, 39, 43, 45, 48, and 55 have been amended. Claim 70 has been added. Claims 1, 4, 6, 13-16, 18, 19, 21-23, 39, 43-45, 48, 49, 55 and 70 are pending and examined on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 14, 48 and 49 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.
Claim 48 requires that the composition of claim 1 comprises a surfactant. Claim 49 requires that the surfactant is at a concentration including 0 mg/ml. It is unclear how claim 48 can require a surfactant if the concentration of the surfactant is 0 mg/ml.
Claim 14 is vague and indefinite in its dependence on canceled claim 3. For purpose of examination, claim 14 will be read as dependent on claim 13.
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.
Claim 70 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
(a) As drawn to prevention.
Claim 70 is drawn in part to a method for preventing a tumor or an infectious disease comprising the administration of the composition of claim 1 to a subject in need thereof. When given the broadest reasonable interpretation, the subject in need thereof includes a human or non-experimental animal in need of prevention or treatment of any infectious disease or tumor. In order for prevention to occur in the case of a PD-L1 expressing tumor, the antigen-binding fragment that binds to PD-L1 must be present in the subject at a therapeutically effective amount before the tumor occurs, or before it is expressed during an infection. The antigen-binding fragment of the composition of claim 1 would have a finite lifetime in vivo and would not be expected to maintain a therapeutically effective amount in circulation during the whole of this lifetime. Thus, one of skill in the art would have to know when a tumor or infectious disease will be occurring in a subject such that the composition can be administered prior to the occurrence.
(b) As drawn to the treatment of infectious diseases
When given the broadest reasonable interpretation, the treatment of an infectious disease encompasses the treatment of any acute or chronic infectious disease. Although blockade of the PD-1/PD-L1 pathway can reverse CTL exhaustion in chronic infections of viruses, bacteria, parasites and helminths (Hofmeyer et al, Journal of Biomedicine and Biotechnology, 2011, article 451694, 9 pages, see page 4, second column, lines1-5), it is unclear if blockade of PD-1 by administration of the PD-L1 binding agent would result in treatment of acute infection. During acute viral infection, experimental evidence suggests that insufficient signaling through the PD-1 pathway promotes immunopathology by exaggerating primary T cell responses (Schonrich and Raffery, Frontiers in Cellular Infection Microbiology, 2019, Vol. 9, article 207, see lines 7-9). Schonrich and Raffery teach that the immune response during an acute viral infection can be dysregulated due to variation of PD-L1 expression, imbalance between co-stimulatory vs co-inhibitory receptors and altered usage of PD-L1 interaction partners (page 5, second column, lines 10-15 of the full paragraph). The specification fails to provide any teachings or guidance regarding these issues above. One of skill in the art would be subject to undue experimentation without reasonable expectation of success in order to carry out the broadly claimed method.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 6, 13-16, 18, 19, 21 and 70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xu et al (U.S. 2018/0327494).
Xu et al disclose a composition comprising an antigen binding fragment comprising an immunoglobulin single-variable domain comprising CDR1-3, wherein CDR1 is SEQ ID NO:4, the CDR2 is SEQ ID NO:11 and the CDR3 is SEQ ID NO:12, which are identical to the instant SEQ ID NO:45, 46 and 47, respectively. Xu et al disclose a pharmaceutical composition comprising the single variable domain, wherein the composition comprises sorbitol (paragraph [0136]) which meets the limitations of claim 1 for an excipient. Xu et al disclose the single-variable domains of SEQ ID NO: 28 and 33-37, which are identical to the instant SEQ ID NO: 1-6., which meets the limitations of claim 4. Xu et al disclose that the antigen-binding fragment comprises an Fc region of an immunoglobulin (paragraphs [0015]-[0028], [0030], [0072], [0188]) and an Fc region derived from human IgG (paragraph [0095]). Xu et al disclose SEQ ID NO: 41, 42, 45 and 51, which meets the limitation of SEQ ID NO: 7 in claim 14, and SEQ ID NO: 78 which meets the limitation of SEQ ID NO: 8 in claim 14. Xu et al disclose antigen-binding fragments of SEQ ID NO: 51, 78, 72, 73, and 74 which are identical to the instant SEQ ID NO: 19, 20, 26, 27, and 28, respectively and which meet the limitations of claim 15. Xu et al disclose concentrations of the antigen-binding fragment in the composition of 100 mg/ml, about 150 mg/ml, about 200 mg/ml or about 250 mg/ml (paragraph [0107]) which meets the limitations of claims 16, 18, 19 and 21.
Xu et al disclose a method for treating cancer or an infectious disease in a subject, comprising administering an effective amount of the PDL1-binding molecule of claim 1 (claims 21 and 27 of ‘494) which meets the limitations of claim 70.
Claim Rejections - 35 USC § 103
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.
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.
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.
Claim 1, 4, 6, 13-16, 18, 19, 21-23, 39, 43-45, 48, 49, 55 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al (U.S. 2018/0327494) in view of Narayan et al (WO2021/240458), Cui et al (Drug Development and Industrial Pharmacy, 2017, Vol. 43, pp. 519-530), Rinaldi et al (WO2015/177057) and Kaisheva et al (WO2003/039485).
Xu et al teach the limitations of claims 1, 4, 6, 13-16, 18, 19, and 21 with regard to a composition comprising the required sequences. Xu et al teach concentrations of the antigen-binding fragment in the composition of 100 mg/ml, about 150 mg/ml, about 200 mg/ml or about 250 mg/ml (paragraph [0107]) which meets the limitation of claim 55, part 1. Xu et al teach that the composition can be formulated for high drug concentration and that the proper fluidity of the resulting composition can be maintained by the use of surfactants (paragraph [0140]).
Xu et al do not teach (i) that the excipient is at a concentration of about 5mM to about 500mM; (ii) that the excipient comprises proline at a concentration of about 50mM to about 390 mM; (iii) that the composition has a pH of about 5.0 to about 7.5; (iv) that the composition comprises a buffering system selected from the group consisting of sodium acetate/acetic acid; histidine/acetic acid; L-histidine/L-histidine hydrochloride, sodium phosphate and citric acid-sodium hydrochloride; (iv) that the buffering component is at a concentration of about 5mM to about 50mM ; (v) that the buffering component comprises acetate-acetic acid at a concentration of about 5 mM to about 35 mM; (vi) that the composition comprises a surfactant which is one or more of polysorbate 20, polysorbate 80 and poloxamer 188; (vii) the surfactant has a concentration of up to 0.8 mg/ml, or (viii) a composition of claim 1 comprising about 10mM to about 30 mM of sodium acetate-acetic acid ; about 150mM to about 250mM of proline; and about 0.2mg/ml to about 0.4 m/ml polysorbate 20, wherein the composition has a pH of about 6.3 to 6.5.
Narayan et al teach a process of preparing a stable formulation comprising first pre-formulating the antibody of interest, a suitable buffer and adjusting the pH of the formulation to pH5 to about 5.9, storing the pre-formulation at freezing temperatures for a suitable length of time; performing a freeze thaw cycle of the pre-formulation, wherein the pre-formulation comprises substantially low aggregates or substantially ow high molecular weight impurities after storage at freezing temperatures; mixing suitable excipients to formulate the final formulation (claim 1 of ‘458), wherein the suitable excipients comprise a buffer selected from phosphate, citrate, phosphate-citrate, histidine, acetate and salts thereof (Claim 17(a) of ‘458) which meets the limitations of claim 43 for an acetate buffer a histidine buffer, a phosphate buffer and a citric acid buffer; and the limitation of claim 55 for an acetate buffer. Narayan et al teach that the excipients further include suitable aggregation inhibitors selected from arginine, arginine HCl, lysine or lysine HCl, glycine and proline (Claim 17(b) of ‘458), which meets the limitations of claim 1 for the excipients of arginine, proline and glycine and claim 55 part 3 for proline. Narayan et al teach that suitable surfactant selected from polysorbate and poloxamer, which meet that part of claim 48 and those limitation in claim 55 part 4.
Cui et al teach that all approved therapeutic mAb as of 2017 are maintained in a slightly acidic environment of pH 5.0 to pH 7.4 which is critical for the physical and chemical stability of the antibody (page 521, second column, lines 4-7) which meets that limitation of claim 39. Cui et al teach that although the type and amount of buffering agent should be determined on a case-to-case basis, the most commonly used buffering agents are phosphate, citrate and histidine salts (page 522, last line of column 1 to line 4 of the second column). Cui et al each that tocilizumab, bevacizumab, alemtuzumab, cetuximab, adalimumab, alemtuzumab, imfliximab, abciximab, basiliximab, eculizimab, natalizimab and daclizumab are formulated with a sodium phosphate buffer (Table 2) which meets the limitation of a buffering component which is sodium phosphate in claim 43; blinatumomab is formulated with a citric acid-sodium hydroxide buffer (Table 2, both of Blincyto and Opdivo) which meets that limitation in claim 43; secukinumab, vedolizumab, canakinumab, Ustekinumab and omalizumab are formulated with L-histidine-L-histidine HCl (Table 2) which meets that limitation in claim 43; pertuzumab is formulated with histidine-acetate (Table 2) which meets the limitations of histidine -acetic acid in claim 43 .
Cui et al teach that tweens are important nonionic surfactants that are widely employed in the pharmaceutical industry and that tween 20 and tween 80 are present in most licensed mAb formulations (page 523, first column, lines 4-6). Tween 20 and tween 80 are also known as polysorbate 20 and polysorbate 80. Cui et al teach that total amount of tween should be optimized to maximize desired surface-active properties and minimize negative effects incurred by exposure to oxygen and heat, but that the amount of tween usually required is relatively small and concentration of less than 0.005% (w/v) are sufficient to prevent aggregation and precipitation (page 523, first column, line 10 to second column, line 2) which meet the limitation of about 0mg/ml to about 0.8mg/ml in claim 49.
Rinaldi et al teach an antibody composition comprising 50mg/ml adalimumab; 10mM sodium acetate/acetic acid and 1 mg/ml polysorbate 80, which meets the limitation of claim 55 part (2) and the amount of antibody in part (1).
Kaisheva et al teach that compositions of the invention minimize the formation of antibody aggregates and particulates and insure that the antibody maintains its bioactivity over time (page 11, lines 3-4). Kaisheva et al teach an antibody composition comprising a high concentration of antibody in a buffer wherein the antibody concentration is 50mg/ml or greater (page 11, lines 8-9) which meets the limitations of part 1 of claim 55, the pH is 5.5 to 6.5 (page 11, lines 3-7) which meets the limitation of a pH of about 5 to about 7.5 in claim 39, a pH from 6.3 to 6.5 in claim 55. Kaisheva et al teach a tonicity modifier, the preferred embodiment of which is proline at 200mM concentration (page 11, line 30 to page 12, line 8), which meets those limitations in claims 22, 23 and part (3) of claim 55, and a surfactant which is polysorbate 20 or 80 at a preferred concentration of about 0.02% to 0.04% (page 11, lines 22-29) which meets the limitations of claims 48, 49 and part 4 of claim 55.
It would have been prima facie obvious at the time of the effective filing date to optimize the combination of prior art excipients using the prior art effective concentrations and concentration ranges, including the aggregation inhibitors selected from arginine, arginine HCl, lysine or lysine HCl, glycine and proline; buffering components including sodium phosphate buffer; citric acid-sodium hydroxide buffer; L-histidine-L-histidine HCl histidine -acetic acid and sodium acetate-acetic acid; surfactants of tween 20 or tween 80, using the concentration ranges from the prior art formulations produce a formulation of the instant claims. One of skill in the art would have been motivated to dos o by the teachings of Narayan et al on the process of preparing a stable formulation by adding appropriate excipients which are buffers, aggregation inhibitors and surfactants; the teachings of Cui et al on commonly used buffering components which are sodium phosphate buffer, citric acid-sodium hydroxide buffer L-histidine-L-histidine HCl and histidine-acetate and surfactants of tween 20 and 80; the teachings of Kaisheva et al regarding a high concentration of antibody in a buffer wherein the antibody concentration is 50mg/ml or greater, the pH is 5.5 to 6.5 and the tonicity modifier, the preferred embodiment of which is proline at 200mM concentration, a surfactant which is polysorbate 20 or 80 at a preferred concentration of about 0.02% to 0.04%; and the teachings of Rinaldi et al on an antibody composition comprising 50mg/ml adalimumab; 10mM sodium acetate/acetic acid and 1 mg/ml polysorbate 80 to arrive at the claimed compositions One of skill in the art would be motivated to use the prior art excipients at the prior art concentration because antibody composition comprising said excipients are already approved by the FDA for therapeutic use and the concentrations were taught to be effective for minimizing aggregation. Further one of skill in the art would have a reasonable expectation of success because the prior art excipients were selected for minimizing aggregation and particulate formation over time in the antibody compositions, thus providing stable formulations.
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, 4, 6, 13-16, 18, 21-23, 39, 43-45, 48, 49, , 55 and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of copending Application No. 19/591,648 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘648 application anticipate the instant claims. Amino acids 31-35, 50-66 and 90-117 of SEQ ID NO: 1 of claim 4 of the ‘648 application anticipate instant claim 1 for the CDR sequences of SEQ ID NO: 45-47, respectively. SEQ ID NO: 5-7 of claim 6 of the ‘648 application are identical to the CDRs of SEQ ID NO: 45-47 of instant claim 1. SEQ ID NO: 1 of claim 7 of the ‘648 application is identical to SEQ ID NO: 2 and thus anticipates instant claim 4. SEQ ID NO: 2 and 3 of claim 10 of the ‘648 application are identical to SEQ ID NO: 7 and 8 of instant claim 14, and thus anticipate instant claims 6, 13 and 14. .SEQ ID NO: 4 of claim 12 of the ‘648 application is identical SEQ ID NO: 21 and thus anticipates instant claim 15. Claim 24 of the ‘648 application anticipates instant claims 16, 18, 19 and 21. Claim 26 anticipates instant claim 39. Claims 27 and 28 anticipate instant claims 43-45. Claim 29 anticipate the excipients of proline, glycine, mannitol, sorbitol, proline, arginine hydrochloride, sucrose and glycerol in instant claim 1. Claim 30 anticipates instant claim 22. Claims 33 and 34 anticipate instant claims 48 and 49, respectively. Claim 35, part (6) anticipates instant claim 23 and claim 55. Claims 36-44 anticipate instant claim 70.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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