DETAILED ACTION
Applicant’s claims filed 10/06/2023 are acknowledged and entered into the record.
Accordingly, Claims 1-18 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 has additional words starting with capital letters other than the first word of the claim. Appropriate correction is required.
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.
Claim 1 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.
The term "sufficient to augment" in claim 1 is a relative term which renders the claim indefinite. The term "sufficient" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-18 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. This is a written description rejection.
Instant Claim 1 broadly reads on a method of treating any patient with any tumor comprising administering any checkpoint inhibitor to said patient and extracorporeally removing any antigen in an amount sufficient to augment an efficacy of the checkpoint inhibitor. Furthermore, the claims are drawn to administering a checkpoint inhibitor capable of suppressing activity of a molecule, but does not provide any structure to function correlation contributing to the suppression of activity, which reads broadly on a range of antibodies, small molecule inhibitors, siRNA, antagonists etc which target checkpoint inhibitors directly or receptors or other pathway molecules that all are capable of “suppressing” activity of said checkpoint inhibitor.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen.
Instant claims 1-81 are drawn to methods of treatment comprising administering a checkpoint inhibitor capable of suppressing activity of molecule. The claims are broadly drawn to a method comprising using a broad genus of inhibitors without describing any structural features common to the members of the genus, which features constitute a substantial portion of the genus.
In regards to the checkpoint inhibitor structures instantly claimed (ex. anti-PD-1 antibodies nivolumab and pembrolizumab), as was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
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 discloses use of checkpoint inhibitors, all of which are antibodies, however the instant claims are drawn to a more broad range of “inhibitors” for treatment. The instant specification does not describe any structure to therapeutic function correlation of the broad scope of “inhibitors” instantly claimed in the methods of treatment. The described species therefore cannot be considered representative of either of the two recited genera of antibodies used in the methods recited in the independent claims. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed suppressing activity, a prerequisite for utility in the recited methods of treatment.
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 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.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Levade et al. (US Patent 10,918,737) in view of Lentz et al. (US PgPub 2005/0265996A1).
The claims are drawn in part to a method of treating or ameliorating the effects of a tumor in a patient comprising administering an anti-PD-1 of anti-PD-L1 antibody and extracorporeally removing a TNF family member from said patient.
Levade et al. teach methods for enhancing the potency of an immune checkpoint inhibitor administering to a subject as part of a treatment regimen for cancer, the method comprising administering a TNF alpha blocking agent in combination with an immune checkpoint inhibitor. In particular, Levade et al. teach, a method of treatment combining a TNF alpha blocking agent with an anti-PD-1 antibody and/or an anti-PD-L1 antibody. Levade et al. disclose anti-TNFR1 synergizes with anti-PD-1 in experimental melanoma (see Fig. 10). Example 2 of Levade et al. teach TNF or TNF-R1 inhibition improves anti-PD-1 therapy against melanoma. Levade et al. further disclose “collectively, our data indicate that TNF-R1-dependent TNF signaling is not required for the anti-melanoma immune response triggered by anti-PD-1 antibodies but rather inhibits the therapeutic benefit of PD-1 blockade in melanoma. Inhibiting TNF or TNF-R1 may therefore facilitates the anti-PD-1 efficacy to fight against melanoma” (see paragraph [0069]). Levade et al. does not teach extracorporeally removing soluble TNF-alpha receptor. This deficiency is made up for by Lentz et al.
Lentz et al. teach methods of treating cancer patients comprising selective removal of soluble TNFR1 and soluble TNFR2 from the blood or plasma of the cancer patient by means of extracorporeal apheresis and wherein the method further comprises treating patients with additional blocking factors. Lentz et al. teach in Example 1, “Secretion of TNF alpha and interleukin 2 that bind via specific receptors to the tumor cell and induce cell death by apoptosis is the normal response of the immune system in its constant fight against cancer growth. However, local secretion of high levels of soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) and interleukin-2 (sIL2R) are believed to be an effective mechanism by the tumor cell to locally block the attack and destruction by the immune system. Systemic removal of these inhibitors by means of extracorporeal apheresis with the goal to reduce the local inhibitor concentrations below the tumor-protective threshold has, therefore, been considered to be a potential therapeutic measure for cancer treatment.”
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treatment taught by Levade et al. to include the method taught by Lentz et al. of removing soluble TNFR1 and soluble TNFR2 to enhance a patient’s immune response and improve anti-PD-1 or anti-PD-L1 efficacy when administered. One of ordinary skill in the art would have been motivated to do so because Levade et al. teach Inhibiting TNF or TNF-R1 facilitates the anti-PD-1 efficacy in cancer patients and Lentz et al. teach removal of soluble TNFR1 and soluble TNFR2 enhances immune response and tumor burden in cancer patients. Therefore, the prior art teach combining blocking TNF and TNF receptor interaction (either via administering an anti-TNF antibody or removal of soluble TNFR1 or soluble TNFR2) and anti-PD-1 and/or anti-PD-L1 improved therapeutic benefit. Thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two modes of treatment, each of which is taught by the prior art to be useful for the same purpose in order to make a protocol that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instantly claimed method of combining extracorporeally removing soluble TNF alpha receptor and administering an anti-PD-1 or anti-PD-L1 antibody for cancer treatment, given the teaching of the prior art, it would have been obvious to combine the teachings of Levade et al. and Lentz et al. for improved therapeutic benefit because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful for the same purpose. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to perform selective removal of soluble TNFR1 and/or soluble TNFR2 and administer anti-PD-1 or anti-PD-L1 to a patient having a tumor based on the teachings of Levade et al. and Engel et al. showing improved therapeutic benefit when done in combination.
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 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.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lentz et al. (US Patent 7,854,717) in view of Kent et al. (Drugs, 74:1993-2013, 2014).
The claims are drawn in part to a method of treating or ameliorating the effect of a tumor in a patient, the method comprising administering an anti-PD1 antibody (nivolumab or pembrolizumab) and extracorporeally removing a tumor necrosis factor (TNF) family member. The claims broadly read on TNF receptors which are included in the TNF family.
Lentz et al. teach methods to treat cancer associated with elevated levels of TNF receptors using ultrapheresis refined to remove compounds of less than 120,000 daltons molecular weight (such as soluble TNFR1 and soluble TNFR2, see claims 1, 10, 11 of Lentz) to stimulate the patient’s immune system to attack solid tumors. Lentz et al. teach these can be removed by standard techniques for binding reactions to remove proteins from the blood or plasma of a patient such as using columns. Lentz et al. teach the treatment is preferably combined with an alternative therapy, for example, treatment with an anti-angiogenic compound, and an improved effect is shown when combined with any treatment that enhances cytokine activity against the tumors. Lentz et al. discloses “[t]his procedure has been demonstrated to cause a significant response (greater than 50% reduction in size of tumors) in a variety of solid tumors in approximately 50% of patients who have failed all other treatment modalities. A tumor specific inflammatory response provoked by ultrapheresis has been documented in approximately 75% of patients in metastatic melanoma clinical trials.” Lentz et al. does not teach specific combination with a checkpoint inhibitor. This deficiency is made up for by Kent et al.
Kent et al. teach that numerous immune checkpoint inhibitors are in advanced stages of development and show activity across multiple tumor types, including advanced melanoma and advanced non-small cell lung cancer (see Table 2). Kent et al. teach checkpoint inhibitors in clinical development including AMP-224 as well as other antibodies which bind PD-1 and suppress PD-L2 activity. Kent et al. teach several other checkpoint inhibitors including anti-PDL1 agents, PD-1 inhibitors and anti-CTLA4 agents, specifically Nivolumab and Pembrolizumab (see Table 1). Kent et al. disclose “[I]t has been postulated that targeted agents and/or cytotoxic chemotherapy that effectively destroy tumor cells may increase circulating tumor antigens and, therefore, increase the immunogenic response and utility of checkpoint inhibitors.” Table 3 of Kent et al. teach ongoing phase II and III trials investigating combination regimens with immune checkpoint inhibitors.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to teach a method of combination therapy comprising the method of extracorporeal removal of soluble TNFR1 and TNFR2 to stimulate a proinflammatory immune response in combination with additional anti-cancer therapy such as administration of a checkpoint inhibitor such as AMP-224, or anti-PD-1 or anti-CTLA4 inhibitors based on the teachings of both Lentz et al. and Kent et al. One of ordinary skill in the art would have been motivated to do so because Lentz et al. teach combining the method of removing soluble TNFR1 and soluble TNFR2 with another treatment that enhances immune response. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two modes of treatment, each of which is taught by the prior art to be useful for the same purpose in order to make a protocol that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instantly claimed method of combining extracorporeally removing soluble TNF alpha receptors and administering a checkpoint inhibitor for cancer treatment, given the teaching of the prior art, it would have been obvious to combine the teachings of Lentz et al. and Kent et al. for improved therapeutic benefit because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful for the same purpose, stimulate an immune response. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to perform selective removal of soluble TNFR1 and/or soluble TNFR2 and administer a checkpoint inhibitor (such as Nivolumab or Pembrolizumab) to a patient having a tumor based on the teachings of Lentz et al. and Kent et al. showing improved therapeutic benefit when such treatments are combined.
Double Patenting Rejection
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,814,430. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and those of US Patent 11,814,430 are both drawn to the same methods.
Conclusion
Claims 1-18 are rejected.
No Claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEERA NATARAJAN whose telephone number is (571)270-3058. The examiner can normally be reached M-F 9AM - 5PM.
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, JULIE WU can be reached on 571-272-5205. 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.
/Meera Natarajan/Primary Examiner, Art Unit 1643
Prosecution Insights