DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 3/3/26. Claims 2, 6, 13-24, 27-29, 32, 34-37, 39-40, 42-43 have been cancelled. Claims 1, 3-5, 7-12, 25-26, 30-31, 33, 38, 41, 44-45 are pending. Claims 1, 44-45 have been amended. Claims 1, 3-5, 7-12, 25-26, 30-31, 33, 38, 41, 44-45 are examined herein.
Applicant’s arguments have been fully considered but found not persuasive. The rejection of the last Office Action is maintained for reasons of record and modified below due to the claim amendments.
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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 3-5, 7-12, 25-26, 30-31, 33, 38, 41, 44-45 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,433,074 in view of Chang et al. (US Patent Application 2016/0018403, of record) and Giesing et al. (US Patent Application 2006/0088840, of record).
Claims 1, 3-5, 7-12, 25-26, 30-31, 33, 38, 41, 44-45 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,433,075 in view of Chang et al. (US Patent Application 2016/0018403, of record) and Giesing et al. (US Patent Application 2006/0088840, of record).
Both referenced claims recite a method of treating glioblastoma in a human subject by administering 4-iodo-3-nitrobenzamide (iniparib) and temozolomide. The referenced claims do not teach the claimed limitations regarding TrxR or PRDX. The teachings and motivation of the secondary references, Chang and Giesing et al., are the same as the 103 rejection below, therefore will also apply here.
Response to Arguments
Applicant makes no substantial arguments in the response, so that the same rejections will apply.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 3-5, 7-12, 25-26, 30-31, 33, 38, 41, 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Blakeley et al. (“Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas,” J. Neurooncol., 2015, 125, 123-131, of record) in view of Chang et al. (US Patent Application 2016/0018403, of record) and Giesing et al. (US Patent Application 2006/0088840, of record).
The instant claims are directed to a method of treating a subject having a cancer by determining whether the subject has an elevated expression of thioredoxin reductase (TrxR) or peroxiredoxin (PRDX) and administering 4-iodo-3-nitrobenzamide (iniparib) and temozolomide.
Blakeley et al. teach a method of treating gliomas by administering iniparib with temozolomide in a subject who had successfully completed radiation therapy. Iniparib was administered twice a week and dose escalated up to 16 mg/kg/week. Blakely et al. also teach that 34 of the patients had glioblastoma (abstract), specifically grade IV (Table 1).
However, Blakely et al. fail to disclose the limitations regarding TrxR or PRDX.
Chang et al. teach methods of using stabilized cancer peptide fragments derived from “redoxin proteins” selected from thioredoxin and peroxiredoxin-1, -2, and -3 for the detection of cancer, diagnoses of cancer, severity of cancer, and effectiveness of a therapeutic regimen comprising detecting and measuring the amount of redoxin peptide fragments present in a biological sample of a subject (abstract). Example 1 shows that the thioredoxin system is composed of the redox-active protein thioredoxin, the enzyme thioredoxin reductase and NADPH. Thioredoxin expression was found to be increased in several primary cancers (paragraph 0057). An embodiment of the invention provides a biomolecule, for example an antibody, that is selective for a redoxin peptide fragment, such as an amino acid sequence consisting of SEQ ID NOS: 1-42 (paragraphs 0020-0021). Methods of monitoring the progression of cancer comprises determining the amount of one or more redoxin peptide fragments present in a biological sample at one or more subsequent time points, and comparing this amount with the amount of one or more redoxin peptide fragments present at the biological sample at the first time point, wherein the higher amount of the subsequent time point compared to the first time point indicates that the cancer has progressed since the first time point, and wherein a lower amount indicates that he cancer has regressed since the first time point (paragraph 0022). The biomolecule may be selected from recombinant antibody, a recombinant monoclonal antibody, a polyclonal antibody, a humanized antibody, and an antibody fragment (paragraph 0037). Various cancers are encompassed by the scope of this invention, including breast, colon, glioma, pancreatic, prostate, etc. (paragraph 0038). The expression level of serum peptide fragments in an individual suspected to suffer from cancer and/or susceptible to cancer will be higher compared to the expression levels of the same marker in a healthy individual due to the over-expression of redoxin-proteins in cancer cells. Since the aggressiveness of cancer is positively related to the production of redox-proteins in cancer cells, measurement of the stabilized serum peptide fragments released from these cancer proteins indicates the severity and invasiveness of cancer (paragraph 0093). To quantify the serum cancer peptide fragment level, a competitive ELISA or a peptide ELISA may be used. An embodiment of a protocol for a competitive ELISA according to the present invention, using a single antibody against the peptide fragment, is taught (paragraph 0094).
Giesing et al. teach methods of determining the expression of thioredoxin reductase as a reliable tumor diagnosis and prognosis in cancer treatment (abstract). The thioredoxin reductase family includes a plurality of thioredoxin reductase isoforms, of which, besides thioredoxin reductase 1, thioredoxin reductase 2 and 3 exists (paragraphs 0057-0058). All the values measured on a test cell are compared to a standard control (paragraph 0107). Sequence-specific primers are used for determining the expression of at least one thioredoxin reductase gene (claim 10). Antibodies can be used in quantitative immunoassays, for example the protein or polypeptide to be detected competes as antigen or labeled antigen for antibody binding (paragraphs 0046, 0119).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have detected, diagnosed, and monitored the effectiveness of a therapeutic regimen by measuring and comparing the expression levels of TrxR and/or PRDX to a control, as taught by Chang and Giesing et al., in the method of treating a brain cancer, such as glioma, by administering iniparib and temozolomide, as taught by Blakeley et al.
A person of ordinary skill in the art would have been motivated to combine the teachings of these cited prior art references because it is important to diagnose and monitor the progression of a cancer in a subject being administered anti-cancer agents. It is important because any physician would need to know if the anti-cancer agents are being effective in treating the cancer over a period of time so as to reduce or eliminate the symptoms of the disease while avoiding unnecessary toxicity and side effects associated with anti-cancer treatment.
It is noted that the limitations regarding the elevated expression levels of TrxR and PRDX in claims 7 and 11 are obvious because the cited prior art teaches methods of measuring the expression levels of both TrxR and PRDX by contacting samples from a subject with cancer by with antibodies, therefore this property will necessarily be the same.
It is also noted that the limitations regarding “wherein the treating reduces a hazard rate of the subject having cancer by at least 25% as compared to a control subject” and “wherein a length of disease free interval (DFI) for the subject having an elevated expression of TrxR or PRDX is extended by at least 25%” are obvious because all elemental steps of the method claim has been taught by the cited prior art. Therefore, this reduction in hazard rate and increase in length of disease free interval will also necessarily occur absent a showing of unexpected results.
Finally, it is also noted that the limitation regarding “wherein the therapeutically effective amount of 4-iodo-3-nitrobenzamide inhibits TrxR activity in an NADPH-dependent manner” is obvious because Blakeley et al. teach a dosage amount (16 mg/kg) that encompassed in dependent claim 25, which recites a range of about 5 mg/kg to about 40 mg/kg. Since Applicant admits on the record that a range of about 5 mg/kg to about 40 mg/kg is a therapeutically effective amount that inhibits TrxR activity in an NADPH-dependent manner, it would be obvious that a dosage amount of 16 mg/kg would similarly produce the same effect or properties.
Response to Arguments
Applicant argues that Blakely et al. does not teach or suggest a method of selecting a subject having grade IV glioblastoma.
This is not persuasive because Blakely et al. clearly teaches in Table 1 that some of the subject has grade IV glioblastoma.
Applicant continues to argue unexpected and surprising results as submitted in the White Declaration under 37 CFR 1.132 filed 1/15/25. Again, the declaration goes into great detail the considerable effort in determining the mechanism of action for iniparib. Applicants were the first to discover that iniparib covalently binds with activated TrxR to inhibit TrxR enzymatic activity, triggering production of reactive oxygen species, which in turn initiates apoptotic cascade events and eventual cell death. The results of the mechanism of action studies with TrxR and PRDX directly translated into positive clinical trial treatment results for targeted patient populations. Table 1, Figure 32, and Examples 4-6 show significant improvement in overall response rates including overall survival rates, specifically a 33% reduction in hazard ratio in iniparib treated patients as compared to control subjects treated with standard of care alone. The declaration states that the significant improvement in outcome in ndGDB and triple negative breast cancer patients having elevated TrxR or PDRX expression following iniparib treatment is both surprising and unexpected in light of iniparib’s development history. Applicant claims to be the first to describe that iniparib reacts with TrxR and PRDX on a molecular level and impacts the cellular oxidative stress response as part of its mechanism of action.
This is not persuasive because the declaration presents data that is not surprising or unexpected, but merely shows that the invention works as intended. Applicant is reminded that iniparib is already well-known in the art to be useful in the treatment of cancer, therefore any new discovery with regard to its mechanism of action does not qualify as evidence of nonobviousness or unexpected results. Regardless, the secondary references teaches that the nexus between between TrxR/PRDX and cancer has been well-established in the art.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Applicant continues to argue that Chang also does not teach or suggest any measurement of expression levels of TrxR or PRDX nor any reduction in hazard rate of subjects having 1-fold elevated expression of TrxR or PRDX relative to control following iniparib treatment. Applicant submits that Chang and Giesing merely discuss measuring such levels but makes no actual measurements.
This is not persuasive because whether actual measurements were made or not matters little, because the cited prior art teaches the importance and reasons why such measurements should be made. Therefore, Chang and Giesing strongly suggest measuring expression levels of TrxR or PRDX and comparing them to a control because it is important to diagnose and monitor the progression of a cancer in a subject being administered anti-cancer agents. It is important because any physician would need to know if the anti-cancer agents are being effective in treating the cancer over a period of time so as to reduce or eliminate the symptoms of the disease while avoiding unnecessary toxicity and side effects associated with anti-cancer treatment.
Applicant is reminded that Blakeley has already established that 4-iodo-3-nitrobenzamide is known in the art to be useful for treating cancers, such as gliomas. Furthermore, Chang and Giesing teach the nexus between elevated expression levels of TrxR and/or PRDX and various cancers, such as glioma. One of ordinary skill in the art would have looked to this nexus because it allows that a physician to detect, diagnose, and monitor the effectiveness of a drug by measuring and comparing these biomarkers to a control. Again, the motivation comes from the importance of diagnosing and monitoring the progression of a cancer in a subject being administered a drug. It is important because any physician would need to know if the anti-cancer agents are being effective in treating the cancer over a period of time so as to reduce or eliminate the symptoms of the disease while avoiding unnecessary toxicity and side effects associated with anti-cancer treatment. It is also predictable because the effectiveness of 4-iodo-3-nitrobenzamide as an anti-cancer drug and the nexus between TrxR/PRDX and cancer has been well-established in the art.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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