DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed May 25, 2026 is pending.
Claims 2-6, 8-10, 12, 14-29, 32-36, 38-47, 49, 51-54, 56-77, 80-82, 84, 86-88, 91, 93-96, 98-113, 115-117, 120-123, 125-131, and 133-209 are canceled.
Claims 1, 7, 11, 13, 30, 31, 37, 48, 50, 55, 78, 79, 83, 85, 89, 90, 92, 97, 114, 118, 119, 124, 132, and 210-216 are pending.
Claims 1, 13, 83, 89, 132, and 214 are independent claims.
Election/Restriction
The Applicant’s election without traverse to Group I (claims 1, 7, 11, 30, 31, 37, 48, 50, 55, 78, 79, drawn to a method for allowing infiltration of immune cells in a tumor microenvironment, the method comprising administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragment thereof comprising SEQ ID NOs: 1-6); and the species of the anti-clusterin antibody being administered as a monotherapy, an immune checkpoint inhibitor as the immunotherapy, an immunologically cold tumor in the reply filed on May 25, 2026 is acknowledged.
Claims 7, 13, 55, 83, 85, 89, 90, 92, 97, 114, 118, 119, 124, 132 and 210-216 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1, 11, 30, 31, 37, 48, 50, 78, and 79 are currently under consideration.
Specification
The specification is objected to because the phrase “from a patient with metastatic thyroid cancer and form a patient with inoperable metastatic gastric cancer” should recite “from a patient with metastatic thyroid cancer and from a patient with inoperable metastatic gastric cancer” on page 64, paragraph 4 of the specification.
The listing of references on page 79 of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicants’ cooperation is requested in correcting any errors of which Applicants may become aware.
Claim Objections
Claims 1, 11, 30, 31, 37, and 78 are objected to because of the following informalities:
Claims 1, 11, 30, 31, 37, and 78 are objected to since “antigen binding” should be hyphenated in all occurrences.
Claim 78 recites “wherein the treatment comprises administering immunotherapy after one or more cycle of the anti-clusterin antibody or antigen binding fragment thereof or of combination therapy” where it should recite “wherein the treatment comprises administering an immunotherapy after one or more cycles of the anti-clusterin antibody or antigen binding fragment thereof alone or in combination with docetaxel” in lines 1-3.
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.
Claims 37, 78, and 79 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 37 recites “wherein the subject is treated with:” in line 1. Claim 37 depends on claim 1 which recites that the anti-clusterin antibody is “administered to” the subject but not that the subject is “treated with” the anti-clusterin antibody. Therefore, it is unclear if the dosages of the anti-clusterin antibody recited in claim 37 are referring to or are in addition to the administration of the anti-clusterin antibody recited in claim 1. If they are referring to the administration of the anti-clusterin antibody recited in claim 1, the claim lacks antecedent basis.
Amending claim 37 to recite “wherein the subject is further treated with:” or “wherein:” would obviate this part of the rejection.
Claim 78 recites “wherein the treatment comprises administering immunotherapy after one or more cycle of the anti-clusterin antibody or antigen binding fragment thereof or of combination therapy” in lines 1-3. Claim 78 is dependent on claim 1 which recites that the anti-clusterin antibody is administered to a subject but it does not recite that this is done in a “cycle.” Therefore, the phrase “after one or more cycle of the anti-clusterin antibody or antigen binding fragment thereof” lacks antecedent basis and renders claim 78 indefinite.
Amending claim 78 to recite “wherein the treatment further comprises administering immunotherapy after the administration of the anti-clusterin antibody or antigen binding fragment thereof or of combination therapy” would obviate this part of the rejection.
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, 11, 30, 31, and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tremblay et al. 2011 (Cancer Res (2011) 71 (8_Supplement): LB-33, an IDS reference filed 06/07/2024).
In view of the Applicant’s election, independent claim 1 is drawn to method for allowing infiltration of immune cells in a tumor microenvironment, the method comprising administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragment thereof comprising a light chain variable region comprising a light chain complementarity determining region (CDRL) 1 having the amino acid sequence set forth in SEQ ID NO: 1, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a heavy chain complementarity determining region (CDRH) 1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6, wherein the anti-clusterin antibody or an antigen binding fragment thereof is administered alone.
Dependent claim 11 limits the anti-clusterin antibody or antigen binding fragment thereof to that which comprises a) a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:9 and a heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:10; or b) a light chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:11 and a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:12.
Dependent claim 30 limits the method to that wherein the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of between approximately 3 mg/kg to approximately 20 mg/kg.
Dependent claim 31 limits the method to that wherein the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg, at a dose of approximately 9 mg/kg and/or at a dose of approximately 12 mg/kg.
Dependent claim 48 limits the subject to one that has a carcinoma or a metastatic carcinoma.
Regarding claims 1 and 11, Tremblay et al. teach administering the monoclonal antibody, AB-16B5, which interacts with a specific EMT-inducing domain in secreted clusterin (sCLU) (e.g. see Abstract). It is noted that the AB-16B5 antibody comprises the amino acid sequences of the instantly claimed CDRs (claim 1) and the VH and VL and heavy and light chains (claim 11) (e.g. see instant specification pages 80 and 81 of Table 9).
Regarding claim 48, Tremblay et al. also teach that the AB-16B5 reduced the invasion of tumors in models of metastatic breast cancer suggesting that the antibody blocked EMT in vivo (e.g. see Abstract). Tremblay et al. further teach that in their in models of prostate cancer, DU145 and PC-3 prostate cancer cells implanted in SCID mice grew slower in the groups treated with AB-16B5 as a monotherapy or in combination with docetaxel. Tremblay et al. teach that this observation suggested that blocking sCLU with AB-16B5 enhanced the chemo-responsiveness to cytotoxic drugs. Immunohistochemical examination of sections prepared from the prostate tumors exposed to AB-16B5 showed an increase in E-cadherin, a marker of epithelial cells, and a reduction of vimentin, a marker of mesenchymal cells, which indicated that EMT was blocked or even reversed in vivo (e.g. see Abstract).
Further regarding claim 48, Tremblay et al. also teach that AB-16B5 inhibited the invasion of PANC-1 pancreatic cancer cells in vitro (e.g. see Abstract). Similarly, the growth of tumors grown from the NSCLC cell line, A549, was also inhibited by AB-16B5. Tremblay et al. also teach that their studies imply that the combination of increased epithelial character of tumor cells exposed to AB-16B5 coupled with a reduction in the activation of survival pathways contribute to an increase in the sensitivity to chemotherapy and a significant reduction of tumor growth, in particular in cancer types such as pancreatic cancer, where EMT likely contributes to increased chemo-resistance (e.g. see Abstract).
Regarding claims 30 and 31, Tremblay et al. also teach that AB-16B5 is administered at a dose of 10mg/kg (e.g. see Abstract).
It is noted that claim 1 recites “[a] method for allowing infiltration of immune cells in a tumor microenvironment” in the preamble followed by only a single method step (administering to a subject in need thereof the anti-clusterin antibody or an antigen binding fragment thereof alone) in the body of the claim.
The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966.
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020).
During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963). See MPEP 2111.02.II.
This applies to the instant case where the preamble does not distinctly define of any of the claimed invention’s limitations nor does the purpose or intended use recited in the preamble of claim 1 result in a structural or manipulative difference between the anti-clusterin antibody or the step of administrating the anti-clusterin antibody of the claimed invention and the teachings of Tremblay et al. Therefore, the instantly claimed method only encompasses the single method step of administering to a subject in need thereof the anti-clusterin antibody or an antigen binding fragment thereof alone. Thus, for the purpose of applying prior art, the prior art only needs to recite this single step which Tremblay et al. does.
Nonetheless, the intended purpose of “allowing infiltration of immune cells in a tumor microenvironment” as recited in the preamble of claim 1 is an inherent property of the instantly claimed anti-clusterin antibody. While Tremblay et al. is explicitly silent on this property, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Tremblay et al. is explicitly silent with regard to the anti-clusterin antibody 16B5 having the property recited in the preamble of claim 1, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the anti-clusterin antibody 16B5 taught by Tremblay et al. would have the property recited in the preamble of claim 1.
When a claim recites using an old composition or structure (e.g., anti-clusterin antibody 16B5) and the use is directed to a result or property of that composition or structure (property recited in the preamble of claim 1) then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
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 that which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
Claims 1, 30, 31,and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Tremblay et al. 2011 (Cancer Res (2011) 71 (8_Supplement): LB-33, an IDS reference filed 06/07/2024).
Dependent claim 37 limits the method to that the subject is treated with: a/b) the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once weekly; c/d) the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 9 mg/kg once weekly; or e/f) the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 6 mg/kg once weekly.
The teachings of Tremblay et al. are outlined in the 102 rejection above.
Tremblay et al. do not teach that the anti-clusterin antibody or antigen binding fragment thereof is administered one weekly.
Determination of the optimal intervals of treatment and the dosage regimen of a known drug was well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as recites in claim 37, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 50, 78, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Tremblay et al. 2011 (Cancer Res (2011) 71 (8_Supplement): LB-33, an IDS reference filed 06/07/2024) in view of Romeo et al. 2019 (Cells 2019, 8, 460, 1-20, an IDS reference filed 06/07/2024).
Dependent claim 50 limits the subject to one that has or is selected for having a tumor characterized as immunologically cold.
Dependent claim 78 limits the method that wherein the treatment comprises administering immunotherapy after one or more cycle of the anti-clusterin antibody or antigen binding fragment thereof or of combination therapy.
Dependent claim 79 limits the immunotherapy to an immune checkpoint inhibitor.
The teachings of Tremblay et al. are outlined in the 102 rejection above.
Tremblay et al. do not teach that the subject has an immunologically cold tumor; the subject is also administered an immunotherapy after the anti-clusterin antibody; or that the immunotherapy is an immune checkpoint inhibitor.
Regarding claim 50, it is noted that the Applicant has defined an "immunologically cold" tumor as one where the tumor microenvironment is not sufficiently infiltrated by immune cells (especially by lymphocytes) or when the tumor microenvironment is not inflamed (e.g. see page 23 of the instant specification).
Further regarding claim 50, Romeo et al. teach that there is an association between EMT and a reduced infiltration of immune cells (i.e., a predominantly immune-excluded TME) and EMT markers associate with a TME that has inhibitory effects (through immune exclusion or deviation) on antitumor immune responses (e.g. see page 3, second paragraph). Romeo et al. also teach an EMT in tumor cells can have direct effects on cells of the immune system including immune exclusion, i.e., reduced tumor infiltration of immune cells that mediate effective antitumor immune responses (e.g. see page 5, first paragraph).
Regarding claims 78 and 79, Romeo et al. teach that upregulation in tumor cells of inhibitory immune checkpoint molecules of native and adaptive immunity can also occur in tumor cells in response to EMT (e.g. see page 3, fifth paragraph). These molecules inhibit the onset or the continuation of ongoing antitumor immune responses. EMT has been associated with the upregulation of several inhibitory immune checkpoint molecules, such as PD-L1, TIM-3, B7-H3, B7-H1, or CD47. Interestingly, some of these immune checkpoint molecules have been shown to act by themselves as EMT inducers and promote the acquisition of tumor-initiating potential, thereby contributing to the amplification of the EMT process and its associated functionalities (e.g. see page 3, fifth paragraph).
Romeo et al. also teach promising approaches for interrupting the cross-talk between EMT cells and immune cells including investigating antibodies targeting inhibitory immune checkpoints (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4) (e.g. see page 12, fourth paragraph). These antibodies have represented a turning point in cancer therapy. The mechanism of action that is generally ascribed to these drugs is restoring an efficient antitumor immune response. As discussed before, the induction of EMT tumor cells is mainly induced by deviated immune cells (e.g., Tregs, DCregs, MDSCs, M2-polarized TAMs), and it is reasonable to expect that restoring a non-deviated, efficient antitumor immune response may also have favorable consequences on the induction of tumor cell EMT (e.g. see page 12, fourth paragraph).
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 have modified the teachings of Tremblay et al. to incorporate the teachings of Romeo et al. to include that the subject has an immunologically cold tumor; the subject is also administered an immunotherapy after the anti-clusterin antibody; and that the immunotherapy is an immune checkpoint inhibitor. This is because EMT in tumor cells directly reduces the infiltration of immune cells that mediate effective antitumor immune responses and it is reasonable to expect that restoring a non-deviated, efficient antitumor immune response by administering immune checkpoint inhibitor antibodies may have favorable consequences on the induction of tumor cell EMT.
Regarding claim 50, given that the Applicant has defined "immunologically cold" tumors as those where the tumor microenvironment is not sufficiently infiltrated by immune cells; EMT in tumor cells directly reduces the infiltration of immune cells that mediate effective antitumor immune responses and there is a desire to overcome this (Romeo et al.); and AB-16B5 is able to block or even reverse EMT in tumor cells (Tremblay et al.); it would have been obvious to one of ordinary skill in the art to apply the AB-16B5 antibody taught by Tremblay et al. on an immunologically cold tumor with a reasonable expectation of success. A skilled artisan would have reasonably expected that the AB-16B5 antibody, which has already been shown to reduce or even reverse EMT, would be able to increase the infiltration of the TME by immune cells given that EMT is known to directly excludes immune cells from the TME.
Regarding claims 78 and 79, given that EMT has been associated with the upregulation of several inhibitory immune checkpoint molecule; immune checkpoint antibodies are known to restore an efficient antitumor immune response; and it is reasonable to expect that restoring a non-deviated, efficient antitumor immune response by administering an immune checkpoint antibody may have favorable consequences on EMT-mediated properties (Romero et al.); it would have been obvious to one of ordinary skill in the art to further include an immune checkpoint antibody after the administration of the AB-16B5 antibody with a reasonable expectation of success. A skilled artisan would have reasonably expected that addition of an immune checkpoint antibody to the administration of the AB-16B5 antibody would further enhance the anti-tumor response to the now immune cell-infiltrating TME mediated by the AB-16B5 antibody.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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, 11, 30, 31, 37, 48, 50, 78, and 79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9,512,211 (the ‘211 Patent, an IDS reference filed 06/07/2024) in view of Tremblay et al. 2011 (Cancer Res (2011) 71 (8_Supplement): LB-33, an IDS reference filed 06/07/2024) and Romeo et al. 2019 (Cells 2019, 8, 460, 1-20, an IDS reference filed 06/07/2024).
The instant claims are drawn to method for allowing infiltration of immune cells in a tumor microenvironment, the method comprising administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragment thereof comprising a light chain variable region comprising a light chain complementarity determining region (CDRL) 1 having the amino acid sequence set forth in SEQ ID NO: 1, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a heavy chain complementarity determining region (CDRH) 1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6, wherein the anti-clusterin antibody or an antigen binding fragment thereof is administered alone.
The claims in the ‘211 Patent are drawn to (1) a method of reducing the growth of a cancer cell expressing clusterin or of reducing volume of a tumor comprising cells expressing or secreting clusterin and (2) a method of treating carcinoma, the methods comprising administering an antibody or an antigen binding fragment thereof capable of specific binding to clusterin to a mammal in need thereof, wherein the antibody or antigen binding fragment thereof comprises: a. a light chain variable region as set forth in SEQ ID NO.:8 and a heavy chain variable region as set forth in SEQ ID NO.:7; b. a light chain variable region as set forth in SEQ ID NO.:8 and a heavy chain variable region as set forth in SEQ ID NO.:29 or; c. a light chain variable region as set forth in SEQ ID NO.:25 and a heavy chain variable region as set forth in SEQ ID NO.:7.
The claims in the ‘211 Patent differ from the instant invention by failing to recite (1) only the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8); (2) a method for allowing infiltration of immune cells in a tumor microenvironment; (3) the specific dosing regimen recited in claims 31, 31, and 37; (4) that the subject has an immunologically cold tumor; (5) the subject is also administered an immunotherapy after the anti-clusterin antibody; or (6) the immunotherapy is an immune checkpoint inhibitor.
It is noted that SEQ ID NOs: 8 and 7 are identical to instant SEQ ID NOs: 9 and 10, respectively. See sequence alignments below.
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Alignment of the ‘211 Patent’s SEQ ID NO: 8 and instant SEQ ID NO: 9:
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Alignment of the ‘211 Patent’s SEQ ID NO: 7 and instant SEQ ID NO: 10:
The teachings of Tremblay et al. and Romeo et al. are outlined in the 102 and 103 rejections above, respectively.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘211 Patent and to incorporate the teachings of Tremblay et al. and Romeo et al. to include (1) only the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8); (2) a method for allowing infiltration of immune cells in a tumor microenvironment; (3) the specific dosing regimen recited in claims 31, 31, and 37; (4) that the subject has an immunologically cold tumor; (5) the subject is also administered an immunotherapy after the anti-clusterin antibody; and (6) the immunotherapy is an immune checkpoint inhibitor. This is because the humanized anti-clusterin antibody taught by the ‘211 Application is identical to the instantly claimed antibody and that taught by Tremblay et al. (16B5) which shows an ability to block or even reverse EMT (Tremblay et al.).
Regarding claims 1, 11, 48, and 50, given that AB-16B5 is identical to the instantly claimed antibody and the ‘211 Patent’s antibody; AB-16B5 has been show to block or even reverse EMT (Tremblay et al.); EMT in tumor cells directly reduces the infiltration of immune cells that mediate effective antitumor immune responses and there is a desire to overcome this (Romeo et al.); and the Applicant has defined "immunologically cold" tumors as those where the tumor microenvironment is not sufficiently infiltrated by immune cells; it would be obvious to one of ordinary skill in the art to apply the AB-16B5 antibody of the ‘211 Patent in method for allowing infiltration of immune cells in a tumor microenvironment with a reasonable expectation of success. A skilled artisan would reasonably expect that the AB-16B5 antibody, which has already been shown to reduce or even reverse EMT, to be able to increase in infiltration of the TME by immune cells given that EMT directly excludes immune cells from the TME.
Regarding the specific selection of the humanized 16B5 antibody, it would be obvious to one of ordinary skill in the art, with intention of administering the antibody to a human subject, to specifically select the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8) from the ‘211 Patent with a reasonable expectation of success. A skilled artisan would readily understand than the non-humanized antibody could induce an unwanted immunological response to the antibody itself thereby reducing its therapeutic efficacy.
Regarding claims 30, 31, and 37, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art and the ‘211 Patent, the differences would be appear minor in nature. Although the prior art and the ‘211 Patent do not teach all the various permutations of interval ranges as recites in claims 30, 31, and 37, it is conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claims 78 and 79, given that EMT has been associated with the upregulation of several inhibitory immune checkpoint molecule; immune checkpoint antibodies are known to restore an efficient antitumor immune response; and it is reasonable to expect that restoring a non-deviated, efficient antitumor immune response by administering an immune checkpoint antibody may also have favorable consequences on EMT-mediated properties (Romero et al.); it would be obvious to one of ordinary skill in the art to further include an immune checkpoint antibody after the administration of the AB-16B5 antibody with a reasonable expectation of success. A skilled artisan would reasonably expect that addition of an immune checkpoint antibody to the administration of the AB-16B5 antibody would further enhance the anti-tumor response to the now immune cell-infiltrating TME mediated by the AB-16B5 antibody.
Therefore, the claims in the ‘211 Patent would render the instant claims obvious.
Claims 1, 11, 30, 31, 37, 48, 50, 78, and 79 are (provisionally) rejected on the ground of nonstatutory double patenting as being unpatentable over the claims U.S. Patents and copending Applications in view of Tremblay et al. 2011 (Cancer Res (2011) 71 (8_Supplement): LB-33, an IDS reference filed 06/07/2024) and Romeo et al. 2019 (Cells 2019, 8, 460, 1-20, an IDS reference filed 06/07/2024) for similar reasons to the ‘211 Patent above.
The instant claims are drawn to method for allowing infiltration of immune cells in a tumor microenvironment, the method comprising administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragment thereof comprising a light chain variable region comprising a light chain complementarity determining region (CDRL) 1 having the amino acid sequence set forth in SEQ ID NO: 1, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a heavy chain complementarity determining region (CDRH) 1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6, wherein the anti-clusterin antibody or an antigen binding fragment thereof is administered alone.
Claims 1-14 of U.S. Patent No. 8,802,826 (an IDS reference filed 06/07/2024) are drawn to isolated antibody or antigen binding fragment thereof, comprising a light chain variable region as set forth in SEQ ID NO.: 8 and a heavy chain variable region as set forth in SEQ ID NO.: 7, wherein the antibody or antigen binding fragment thereof binds clusterin; a pharmaceutical composition; and a combination therapy.
Claims 1-17 of U.S. Patent No. 9,822,170 (an IDS reference filed 06/07/2024) are drawn to a method of treating carcinoma comprising administering an anti-clusterin antibody or an antigen binding fragment thereof that binds to amino acids 421 to 443 of human clusterin and that is capable of inhibiting epithelial-to-mesenchymal transition (EMT); and a method for reducing the growth of carcinoma cells comprising administering an anti-clusterin antibody or an antigen binding fragment thereof that binds to amino acids 421 to 443 of human clusterin and that is capable of inhibiting epithelial-to-mesenchymal transition (EMT).
Claims 2, 4, 6-9, 11, 14, 22, 24, 25, 31, 33, 40, 50, 54, 60, 63, 67, and 75 of U.S. Application No. 18/287,334 are drawn to a method of treating a subject having cancer, the method comprising administering a preparation of tumor infiltrating lymphocytes (TILs) comprising TILs obtained from the subject's tumor, wherein the subject has received prior treatment with an anti-cancer therapy that comprises an anti-clusterin antibody or antigen binding fragment thereof, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a light chain complementarity determining region (CDRL) 1 having the amino acid sequence set forth in SEQ ID NO:1, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a heavy chain complementarity determining region (CDRH) 1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6; and a method of treating a subject having cancer.
Claims 19-25, 29, 32, 39, 47, 50, 56, 67, 68, and 87-95 of U.S. Application No. 18/287,331 are drawn to a method for allowing infiltration of immune cells in a tumor microenvironment, the method comprising administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragment thereof comprising a light chain variable region comprising a light chain complementarity determining region (CDRL) 1 having the amino acid sequence set forth in SEQ ID NO: 1, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a heavy chain complementarity determining region (CDRH) 1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6. wherein the anti-clusterin antibody or an antigen binding fragment thereof is administered alone or in combination with radiation therapy or with chemotherapy; a combination therapy; a method for treating a subject in need having cancer; a method for allowing infiltration of immune cells in a tumor microenvironment.
The claims in the above Patents and copending Applications differ from the instant invention by failing to recite (1) only the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8); (2) a method for allowing infiltration of immune cells in a tumor microenvironment; (3) the specific dosing regimen recited in claims 31, 31, and 37; (4) that the subject has an immunologically cold tumor; (5) the subject is also administered an immunotherapy after the anti-clusterin antibody; or (6) the immunotherapy is an immune checkpoint inhibitor.
The teachings of Tremblay et al. and Romeo et al. are outlined in the 102 and 103 rejections above, respectively.
It would be obvious to one of ordinary skill in the art to modify the claims in the above Patents and copending Applications and to incorporate the teachings of Tremblay et al. and Romeo et al. to include (1) only the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8); (2) a method for allowing infiltration of immune cells in a tumor microenvironment; (3) the specific dosing regimen recited in claims 31, 31, and 37; (4) that the subject has an immunologically cold tumor; (5) the subject is also administered an immunotherapy after the anti-clusterin antibody; and (6) the immunotherapy is an immune checkpoint inhibitor. This is because the humanized anti-clusterin antibody taught by the above Patents and copending Applications is identical to the instantly claimed antibody and that taught by Tremblay et al. (16B5) which shows an ability to block or even reverse EMT (Tremblay et al.).
Regarding claims 1, 11, 48, and 50, given that AB-16B5 is identical to the instantly claimed antibody and the above Patents and copending Applications’ antibody; AB-16B5 has been show to block or even reverse EMT (Tremblay et al.); EMT in tumor cells directly reduces the infiltration of immune cells that mediate effective antitumor immune responses and there is a desire to overcome this (Romeo et al.); and the Applicant has defined "immunologically cold" tumors as those where the tumor microenvironment is not sufficiently infiltrated by immune cells; it would be obvious to one of ordinary skill in the art to apply the AB-16B5 antibody of the above Patents and copending Applications in method for allowing infiltration of immune cells in a tumor microenvironment with a reasonable expectation of success. A skilled artisan would reasonably expect that the AB-16B5 antibody, which has already been shown to reduce EMT, to be able to increase in infiltration of the TME by immune cells given that EMT directly excludes immune cells from the TME.
Regarding the specific selection of the humanized 16B5 antibody, it would be obvious to one of ordinary skill in the art, with intention of administering the antibody to a human subject, to specifically select the humanized anti-clusterin antibody (i.e. comprising only SEQ ID NOs: 7 and 8) from the above Patents and copending Applications with a reasonable expectation of success. A skilled artisan would readily understand than the non-humanized antibody could induce an unwanted immunological response to the antibody itself thereby reducing its therapeutic efficacy.
Regarding claims 30, 31, and 37, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art and the above Patents and copending Applications, the differences would be appear minor in nature. Although the prior art and the above Patents and copending Applications do not teach all the various permutations of interval ranges as recites in claims 30, 31, and 37, it is conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claims 78 and 79, given that EMT has been associated with the upregulation of several inhibitory immune checkpoint molecule; immune checkpoint antibodies are known to restore an efficient antitumor immune response; and it is reasonable to expect that restoring a non-deviated, efficient antitumor immune response by administering an immune checkpoint antibody may also have favorable consequences on EMT-mediated properties (Romero et al.); it would be obvious to one of ordinary skill in the art to further include an immune checkpoint antibody after the administration of the AB-16B5 antibody with a reasonable expectation of success. A skilled artisan would reasonably expect that addition of an immune checkpoint antibody to the administration of the AB-16B5 antibody would further enhance the anti-tumor response to the now immune cell-infiltrating TME mediated by the AB-16B5 antibody.
Therefore, the claims in the above Patents and copending Applications would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection for the co-pending Application because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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