Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status
Claims 1-4, 10-13, 15-18 and 21-25 are pending. Claims 2, 3, 11, 21 and 22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species. Therefore, Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are under examination.
Election/Restriction
This application contains claims directed to the following patentably distinct species the multitude of non-Hodgkin’s Lymphoma (NHLs). The species are independent or distinct because pathoetiological and pathophysiological factors between each species. In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, Claim 1 is generic.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply:
different field of search: it is necessary to search for one of the inventions in a manner that is not likely to result in finding art pertinent to the other inventions (e.g., searching different classes/subclasses or electronic resources, employing different search queries, etc.).
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
During a telephone conversation with Nicolas Pace on 3/16/2026 a provisional election was made without traverse to prosecute the invention of Burkitt’s lymphoma, claim 1, 4, 10, 12, 13, 15-18 and 21-25. Affirmation of this election must be made by applicant in replying to this Office action. Claims 2, 3, and 11 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Prosecution on the merits will be restricted to the claimed species if no generic claim is finally held to be allowable.
Priority
This application is a continuation of U.S. Application No. 16/808,513, filed March 4, 2020, which is a continuation of U.S. Patent Application No. 16/454,835, filed June 27, 2019 (now abandoned), which is a continuation of U.S. Patent Application No. 16/181,747, filed November 6, 2018 (now abandoned), which is a continuation of U.S. Patent Application No. 15/319,535, filed December 16, 2016 (now U.S. Patent 10,166,238), which is a U.S. National Phase Application, filed under 35 U.S.C. § 371, of International Application No. PCT/US2015/036310, filed June 17, 2015, which claims the benefit of and priority to U.S. Patent Application Nos. 62/013,522, filed June 17, 2014; and 62/036,265, filed August 12, 2014.
Information Disclosure Statement
The Information Disclosure Statement filed 12/15/2023 has been considered by the Examiner. The submission is in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Specification
The disclosure is objected to because of the following informalities: the abbreviation “EZH2” should be spelled out at least once. For example, the term “EZH2” at 002 should be changed to --- Enhancer of zeste homolog 2 (EZH2). Appropriate correction is required.
Claim Objections
Claim 1 and 25 are objected to because of the following informalities:
The abbreviation “EZH2” should be spelled out the first time it appears in the claims. Therefore, the term “EZH2” at line 2 should be changed to --- Enhancer of zeste homolog 2 (EZH2).
The term “the EZH2 inhibitor” should be changed to --- wherein the EZH2 inhibitor
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
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, 4, 10, 12, 13, 15-18 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kuntz et. Al (US 8,410,088 B2, April 02, 2013 – submitted with 12/15/2023 IDS) in view of Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat – and methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
While Kuntz teaches EZH2 inhibitors such as tazemetostat for treating lymphoma, Kuntz does not expressly teach Burkitt’s lymphoma (BL).
However, it was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because:
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression and
2) Kuntz teaches EZH2 inhibitors such as tazemetostat are effective for treating lymphoma.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
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.
A. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 8,410,088 B2 (“reference claims” or “Kuntz”; April 02, 2013 – submitted with 12/15/2023 IDS) in view of Yu et al. (WO 2014/077784 A1, May 22, 2014). NOTE: the specification of U.S. Patent No. 8,410,088 B2 is available as prior art.
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims of Kuntz teach compounds, including the structure of tazemetostat (elected) in reference claim 11, and pharmaceutical products containing the compounds. The compounds are EZH2 inhibitors that are useful for treating lymphoma including NHL. See Kuntz, column 8:52 to column 9:13; see also column 9:~40-46. Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat – and methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
While the reference claims teach EZH2 inhibitors such as tazemetostat and discloses their use for treating lymphoma, the reference does not expressly claim Burkitt’s lymphoma (BL).
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating lymphoma and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
B. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 11-25 of U.S. Patent No. 9,394,283 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a polymorph of tazemetostat (elected) (see reference claim 1), pharmaceutical products containing the compound (see reference claim 11) and a method for treating cancer including lymphoma (see reference claim 12). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:41-46.
While the reference claims teach tazemetostat for treating lymphoma and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating lymphoma and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
C. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9,872,862 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a method for treating a cell proliferative disorder of the lung including cancer by administering an effective amount of a polymorph of tazemetostat (elected). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:46-51.
While the reference claims teach tazemetostat for treating cell proliferative disorder such as cancer of the lung and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating cancer and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
D. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,245,269 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a method for inhibiting histone methyltransferase activity of EZH2 in a subject in need thereof by administering an effective amount of tazemetostat (elected). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:44-53.
While the reference claims teach tazemetostat for inhibiting histone methyltransferase activity of EZH2 and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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304
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for therapeutic effect (treating cancer is specifically taught by Kuntz) and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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446
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
E. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,821,113 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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304
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a polymorph of tazemetostat (elected) and pharmaceutical products containing the compound. The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:44-53.
While the reference claims teach the EZH2 inhibitor tazemetostat and discloses its use for inhibiting EZH2, the reference does not expressly claim Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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318
304
media_image1.png
Greyscale
(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective therapeutic effect (treating cancer is specifically taught by Kuntz) and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
F. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,491,163 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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318
304
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a method for treating a cancer including lymphoma by administering a therapeutically effective amount of a polymorph of tazemetostat (elected). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:~45-55.
While the reference claims teach tazemetostat for treating a cancer such as lymphoma and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
PNG
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318
304
media_image1.png
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating cancer including lymphoma and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
G. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 12,251,386 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a polymorph of tazemetostat (elected) (see reference claim 1), pharmaceutical products containing the compound (see reference claim 11) and a method for treating cancer including lymphoma (see reference claim 12). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:41-46.
While the reference claims teach tazemetostat for treating lymphoma and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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304
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating cancer and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
H. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,166,238 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a method for treating non-Hodgkin’s lymphoma comprising administering an effective amount of an EZH2 inhibitor such as tazemetostat (see reference claim 4), wherein the NHL is primary mediastinal large B-cell lymphoma (PMBCL). The reference claims disclose the effective amounts is in a dose range of about 100-3200 mg/day. See reference claim 1. The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:41-46.
While the reference claims teach tazemetostat for treating lymphoma and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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318
304
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating cancer including NHL and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. The reference claims teach the inhibitor can be administered orally and to a human. See reference claims 2 and 3. Oral compositions are also contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The Kuntz compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600 mg BID. The reference claims teach the inhibitor is administered at a dose of 800 mg BID. See reference claims 6 and 7.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
I. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5, 7, 9, 11, 14-17, 19, 20, 23-25, 27, 35-39 of copending Application No. 18/294,717 (PGPUB US 2024/0335452 A1) (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
This is a provisional nonstatutory double patenting rejection.
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EHZ2 inhibitor.
Prior art
The reference claims teach a method for treating a cancer including non-Hodgkin’s lymphoma (reference claim 38) by administering a therapeutically effective amount of tazemetostat (elected) as an EZH2 inhibitor (reference claims 5 and 15). The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, column 3:~45-55.
While the reference claims teach tazemetostat as an EZH2 inhibitor for treating cancer such as NHL, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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318
304
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors such as tazemetostat are effective for treating cancer including NHL and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
J. Claims 1, 4, 10, 12, 13, 15-18 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8 and 9 of U.S. Patent No. 10,301,290 B2 (“reference”) in view of Kuntz et. Al (US 8,410,088 B2, April 02, 2013– submitted with 12/15/2023 IDS) and Yu et al. (WO 2014/077784 A1, May 22, 2014).
Claimed invention
Claim 1 is directed to a method for treating non-Hodgkin’s lymphoma (NHL), wherein the elected species is Burkitt’s lymphoma (BL), comprising administering to a subject in need thereof, a therapeutically effective amount of
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(i.e., tazemetostat), an EZH2 inhibitor.
Prior art
The reference claims teach a method for treating cancer including lymphoma (see reference claim 9) by administering a compound of formula (IIa)
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288
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. The compound has the utility for inhibiting EZH2 for therapeutic effect. See Specification, abstract.
While the reference claims teach tazemetostat for treating lymphoma and the specification discloses its utility as an EZH2 inhibitor, the reference does not expressly claim treating Burkitt’s lymphoma (BL).
Similar to the patent reference, Kuntz teaches EZH2 inhibitor compounds – including “Compound 44” having the structure
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318
304
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(see Kuntz, column 237), which is Applicant’s elected compound, tazemetostat. Kuntz further teaches methods of treating cancer, including non-Hodgkin’s lymphoma (NHL). See Kuntz, column 9:1-6,~40-47; see also Example 201 at column 405. Kuntz further teaches that such cancers may be associated with EZH2 overexpression or mutation. See Kuntz, column 9:1-6. The Kuntz invention further relates to a method of modulating the activity of wild-type EZH2. See Kuntz, column 9:~20-22. Thus, Kuntz teaches both the claimed compound and its therapeutic use in lymphoma.
It was already known that Burkitt’s lymphoma involves increased activity of EZH2. Yu teaches that EZH2 is upregulated in cancer and mediates epigenetic repression of INFGR1, a component of interferon (IFN)-ɣ signaling. See Yu, 00117. Occurring widely in cancer, EZH2-mediated inactivation of IFN-ɣ signaling confers growth and survival advantages in MYC-dependent cancer cells. See Yu, 00220-00225, 00238. Yu specifically mentions the reverse correlation of EZH2 with IFNGR1 is observed in MYC-driven Burkitt's lymphoma. See Yu, 00239r; see also 0079. This indicates that EZH2 is elevated relative to INFGR1 expression and is functionally active in this disease context.
A person of ordinary skill in the art (POSA) would have found it obvious to administer an effective amount of tazemetostat as an EZH2 inhibitor to treat Burkitt’s lymphoma because
the patent reference and Kuntz teach EZH2 inhibitors (tazemetostat is specifically taught by Kuntz) are effective for treating lymphoma and
Yu teaches Burkitt’s lymphoma is MYC-driven and EZH2 is oncogenically involved in gene regulation in MYC-driven cancer by repressing interferon signaling pathways that are associated with tumor suppression.
The POSA would have recognized EZH2 as a therapeutic target for inhibition in the MYC-driven Burkitt’s lymphoma since EZH2 is known to oncogenically participate in MYC-driven cancer. The POSA would have had a reasonable expectation of success that tazemetostat would impart its inhibitory activity against EZH2 in a subject with Burkitt’s lymphoma to repress EZH2’s inhibitory activity against beneficial interferon signaling.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 limits claim 1, wherein the NHL is Burkitt's lymphoma. Claim 10 limits claim 1, wherein the NHL is an EZH2 wild type B-cell lymphoma. Yu teaches Burkitt’s lymphoma is MYC-driven and does not state it has mutant EZH2 (see Yu, 00239) and Kuntz teaches the EZH2 inhibitors are used to modulate the activity of wild-type EZH2 (see Kuntz, column 9:~20-22).
Claim 12 limits claim 1, wherein the EZH2 inhibitor is administered orally. Claim 13 limits claim 1, wherein the subject is a human being. Oral compositions are contemplated for the EZH2 inhibitors of Kuntz. See Kuntz, column 184:44. The compounds are prepared as a medicament to treat human or non-human animals. See Kuntz, column 8:48-51.
Claims 15-18 and 25
Claim 15-17 limit claim l, wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3200 mg daily (Claim 15), about 100 mg BID to about 1600 mg BID (Claim 16), about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1600 mg BID (Claim 17). Claim 18 further limits claim 17, wherein the EZH2 inhibitor is administered to the subject at a dose of 800 mg BID. Claim 25 limits claim 23, wherein the EZH2 inhibitor is administered to the subject at a dose of approximately 100 mg BID to approximately 1600mg BID. Kuntz teaches treatment at compound (Compound 44 or 87) doses ranging from 12.5-600 mg/kg and at TID (three time a day every 8 h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage. See Kuntz, column 401:64-67. Kuntz also teaches the oral administration of Compound 44 (80.5, 161, 322, and 644 mg/kg). Compound 44 was given once daily on day 1 and day 29 and twice daily every day from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) was calculated from the body weight before administration. A dosing scheme is outlined in Table 6:
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290
446
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. See Kuntz, column 405:~15-60.
Kuntz discloses that dosage amounts may be varied:
“For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.”
See Kuntz, column 183:30-57. Emphasis added.
Given that Kuntz teaches the dosage amounts may vary and further given that the amounts depend on the weight of the subject (e.g., 80.5, 161, 322, and 644 mg/kg) and can be given multiple times a day including BID, the POSA would have found it obvious to adjust the amounts accordingly (disease severity, general health, age, weight, gender) to optimize treatment and would have, thus, found the claimed amounts (e.g., 800 mg BID) to be obvious.
Claim 23 limits claim 1, wherein the NHL is refractory or resistant. Claim 24 limits claim 23, wherein the NHL is resistant at the beginning of treatment. Kuntz teaches the inhibitors are used to alleviate severity of the cancer. See Kuntz column 166:10-64. Cancers which are resistant to traditional treatments are recognized as more severe disease states and remain subject to therapeutic intervention, including treatment to improve outcome and alleviating severity. See Kuntz, 166:49-54. Thus, the prior art recognizes those with resistant cancers as subjects for treatment. The POSA would have found it obvious to apply a known anticancer agent such as tazemetostat to patients identified with resistant or refractory lymphoma prior to treatment, as this represents an extension of cancer therapy to more severe or treatment-resistant forms of the disease taught by Kuntz.
Conclusion
No claims are allowed.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622