DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Receipt and consideration of Applicant’s amended claim set, Applicant’s arguments/remarks, and Declaration Under 37 CFR 1.132 by Niven Narain (Narain Declaration), all submitted on May 23, 2025 are acknowledged.
All rejections/objections not explicitly maintained in the instant office action have been withdrawn per Applicant’s claim amendments and/or persuasive arguments. Applicant’s claim amendments have necessitated new grounds of rejections set forth below.
Status of the Claims
Claims 1, 8, 15, 17, 22-24, 30, 48, 49, 52, 61, and 62 are pending and under consideration in this action. Claims 2-7, 9-14, 16, 18-21, 25-29, 31-47, 50, 51, 53-60, and 63-66 are cancelled.
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, 8, 15, 17, 22-24, 30, 48, 49, 52, 61, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Knox et al. (Knox) (US 2007/0160685 A1; of record), Narain et al. (Narain) (US 2011/0027247 A1; of record), Folkers et al. (Folkers) (Biochemical and Biophysical Research Communications; of record), Thornthwaite (US 2010/0209497 A1; of record), and Voulgaris et al. (Voulgaris) (Am J Clin Oncol; published 2002).
Knox is directed to methods of treating neoplastic disease, particularly drug- and radiation-resistant neoplasms, and particularly for improving the sensitivity of tumors to cancer therapy (para.0007). Knox discloses that the administration of inorganic selenium containing compound (iSe compound), such as inorganic selenite, enhances the sensitivity of a tumor to cancer therapy, such as chemotherapy, and thus increases the efficacy of conventional cancer therapies. The combination therapy with an iSe compound and another cancer therapy provides for a synergistic effect in tumor cell killing, which effect is tumor specific (e.g., the combination does not act in a synergistic manner in killing non-cancerous cells) (para.0025, 0035, 0036, 0038, 0039, 0044, 0096).
Knox provides a method of treating a neoplastic disease in a subject, such as human, by administering an iSe compound in conjunction with a second cancer therapy, such as a cancer chemotherapeutic drug (para.0027, 0070). Exemplary cancer therapies that may be used in combination with the iSe compound therapy include cisplatin, ubiquinone (Coenzyme Q10), and doxorubicin (para.0071, 0072-0075).
Knox defines “in conjunction” to mean to encompass administration of iSe prior to or at the time of administration of the second cancer therapy. Preferably, iSe is administered prior to the administration of the second cancer therapy, and in an amount sufficient to provide for iSe-induced alteration of the tumor cell redox state toward oxidation. The second cancer therapy is then administered after iSe has induced alteration of the tumor cell redox state, e.g., after a time sufficient for metabolism of iSe (para.0077, 0078). The iSe combination therapy of the invention provides the unexpected advantage that iSe compounds provide for sensitization of tumor cells to cancer therapy (e.g., chemotherapy) but not normal cells to a significant degree, particularly where iSe compound is administered prior to administration of the second cancer therapy. In addition, the anti-tumor, tumor-specific effects of iSe compounds are maintained in the presence of the second cancer therapy (para.0079).
In general, the tumors can be solid tumors. The tumors can be of any tissue origin, grade, or stage (para.0088). As Knox discloses that the tumors can be of any stage, the disclosure encompasses tumors of all stages I-IV. The tumors can be associated with cancer of the breast, colon, endometrium, head and neck, lung, skin (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, and the like), digestive system, gastrointestinal system (including colon, rectum, etc.), oral cavity (including lip, mouth, etc.), musculoskeletal system (including muscle, bone, etc.), endocrine system, eye, genitourinary system (e.g., bladder, prostate, ovary, etc.), neurologic system (e.g., brain, etc.), and the like (para.0088).
The methods of the invention can be used to treat primary tumors or metastases. Knox discloses that the invention finds particular use in the treatment of tumors which have proven in a particular patient to be resistant to cancer therapy, e.g., as evidenced by relapse, recurrence, or non-responsiveness to prior cancer therapy. Where the tumor has proved or is known to be resistant to a chemotherapeutic drug, such tumors are often referred to as “drug-resistant” tumors (para.0089).
Knox discloses that of particular interest are the treatment of patients who have failed prior therapy (“treatment failure” patients), which patients either initially responded then relapsed (e.g., did not have sustained remission) or who did not significantly respond (e.g., had tumors that proved resistant to conventional therapy). In an embodiment, the goal is to 1) sensitize tumors to a subsequent cancer therapy by administration of an iSe compound; and/or 2) provide for a synergistic effect on tumor growth inhibition by a combination therapy of an iSe compound administered either prior to or with another cancer therapy (para.0090).
Knox disclose that the therapy involves administration of an amount of iSe compound and dose of a cancer therapy effective to eradicate the tumor when treating with curative intent or achieve local control/palliate symptoms when treating with palliative intent. For example, the therapy can involve killing all of the tumor cells (reading on complete response), shrinking the tumor by killing some of the cells , or controlling tumor growth (e.g., so as to maintain the tumor at its size at the initiation of therapy) (reading on stable disease), by decreasing or delaying tumor growth (para.0098).
With regards to the dosing regimen, when the cancer therapy to be administered in conjunction with iSe compound therapy is a chemotherapeutic drug, administration can be accomplished according to conventional methods. The chemotherapeutic drug can be administered in a single dose or in fractionated doses. For example, chemotherapy is generally administered once about every 2 weeks, 3 weeks or 4 weeks, for a total 4 courses, 5 courses, 6 courses, 7 courses, or 8 courses, with the specific dosing regimen dependent upon a number of factors including the histological type of tumor and stage of disease (para.0098).
Knox does not appear to explicitly disclose administering to the subject a coenzyme Q10 (CoQ10) compound in a sufficient amount such that the subject demonstrates one or more clinical benefits as a result of administration of the CoQ10 compound. Narain, Folkers, Thornthwaite, and Voulgaris are relied upon for this disclosure. Their teachings are set forth herein below.
Narain discloses methods of treating an oncological disorder in a human, comprising administering Coenzyme Q10 (CoQ10) to the human in an amount sufficient to treat the oncological disorder, thereby treating the oncological disorder (abstract; para.0174). The CoQ10 is used to treat solid tumors (para.0180). Examples of cancers amenable to treatment with CoQ10 include, but are not limited to, cancer of the brain, head and neck, prostate, breast, testicular, pancreas, liver, colon, bladder, kidney, lung, non-small cell lung, melanoma, mesothelioma, uterus, cervix, ovary, sarcoma, bone, stomach, and Medulloblastoma (para.0180).
The CoQ10 can be administered by a variety of methods known in the art. Among the preferred route/mode of administration is by intravenous injection (para.0203). The composition may be in the form of liquid solutions (e.g., injectable solutions) (para.0202). Typically, the pharmaceutical composition comprises CoQ10 and a pharmaceutically acceptable carrier, such as water (para.0201). The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structures suitable to high drug concentration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients. In the case of sterile, lyophilized powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants, such as poloxamers (para.0204, 0235).
For injection, the compounds of the invention can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Ringer’s solution (reading on aqueous solution). In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included (para.0205, 0221). The compositions may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents (para.0208). Narain exemplifies liposome dispersions of CoQ10 having an average particle diameter size of about 107 nm (para.0485, 0486), thus reading on CoQ10 being formulated as a nanodispersion.
In an embodiment, the CoQ10 may be topically administered to the human such that treatment occurs, wherein the CoQ10 is topically applied one or more times per 24 hours for six weeks or more (para.0240) (reading on the CoQ10 compound being administered at least one time per week).
The CoQ10 and/or pharmaceutical compositions thereof can be used in combination therapy with at least one other therapeutic agent. The CoQ10 and/or a pharmaceutical composition thereof is administered concurrently, prior to, or subsequent to administration of another therapeutic agent (para.0250, 0278). In an embodiment, the additional agent for use in the therapeutic method is a chemotherapeutic agent. Among the suitable chemotherapeutic agents include doxorubicin (para.0251, 0252).
Narain demonstrates the in vivo effects of CoQ10 administration on pancreatic cancer in their Example 45. An intravenously administered formulation of CoQ10 was evaluated for treating pancreatic cancer in an animal model. Rats with induced pancreatic cancer were randomized into groups and received one of 9 treatments. Narain found that after 28 days, all animals in Groups A (control) and B (saline solution) and the majority of the animals in Group C (vehicle) had died. In contrast, most of the animals in Groups D (5 mg/kg CoQ10), E (10 mg/kg CoQ10), and F (25 mg/kg CoQ10) remained alive, with those animals receiving the higher dose of CoQ10 remaining alive longer. All of the animals receiving the highest dose of CoQ10 (Group G: 50 mg/kg CoQ10) remained alive at 28 days. Narain discloses that these data demonstrate an overall dose response curve in which those animals receiving higher doses had a higher survival rate (para.0777-0787).
To evaluate the effectiveness of CoQ10 in treating pancreatic cancer in combination with doxorubicin, Group H was administered doxorubicin alone, while Group I was administered the combination of Doxorubicin and CoQ10. After 28 days, a significant number of the animals in Group H (5 mg/kg doxorubicin) had died due to the toxicity of doxorubicin, while those animals in Group I (50 mg/kg CoQ10 and 5 mg/kg doxorubicin) had an increased survival rate. Narain discloses that these data suggest that, in addition to increasing the survival rate associated with pancreatic cancer, CoQ10 can also mitigate the toxic side effects of a chemotherapeutic agent (para.0787).
Narain discloses that in an embodiment, the CoQ10 reduces tumor size, inhibits tumor growth, and/or prolongs the survival time of a tumor-bearing subject. Narain also discloses that their invention relates to a method of treating tumors in a human or other animal by administering to such human or animal an effective, nontoxic amount of CoQ10. Narain discloses that one skilled in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of CoQ10 would be for the purpose of treating malignancies. For example, a therapeutically effective amount of CoQ10 may vary according to factors such as the disease stage (e.g., stage I vs. stage IV), age, sex, medical complications (e.g., immunosuppressed conditions or disease), and weight of the subject, and the ability of the CoQ10 to elicit a desired response in the subject. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation (pra.0190).
Thornthwaite discloses that anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering CoQ10 during cancer chemotherapy that includes drugs such as doxorubicin. Studies further suggest that CoQ10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. CoQ10 appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy. CoQ10 showed a strong protective effect on cardiac function during anthracycline therapy (para.0115, 0116).
Folkers discloses case histories of survival of cancer patients on CoQ10 (abstract; pg.243). Patients in heart failure were available who also had cancer and were treated with CoQ10 primarily for their heart failure, but with monitoring of their clinical status of cancer. Folkers discloses that one of these patients on CoQ10 revealed no symptom of heart failure or a positive test for cancer in nine years. Another patient had not even one positive blood test for active cancer during dosage on CoQ10 therapy for three years. Another patient remained on CoQ10 for ten years without recurrence of cancer (pg.245, DISCUSSION).
A 74 year-old male was diagnosed with pancreatic carcinoma in October 1992. His main complaints were back pain, loss of appetite, and weight loss. He had a history of two myocardial infarctions, but had no residual cardiac symptoms and takes no medications. He was started on 266 mg of CoQ10 daily in divided doses. Subjectively, he felt better, his weight loss had stopped, and he maintained his weight. His appetite had returned and he felt that his pain was less (January, 1993) (pg.243, EIGHT NEW CASE HISTORIES OF SURVIVAL OF CANCER PATIENTS ON CoQ10).
A 56 year-old female, diagnosed with cancer, was started on Adriamycin (doxorubicin; topoisomerase II inhibitor) on 9/6/80 and discontinued on 10/20/80 due to cardiotoxicity. CoQ10 was started on 1/4/81 for the treatment of congestive heart failure (CHF) complicated by mitral valve insufficiency. Cardiac function improved significantly and the cancer appeared to be in remission. The patient remained on CoQ10 for ten plus years (4/4/92) without the reoccurrence of cancer or more than Class II CHF (pg.244, para.5).
A 52 year-old female, diagnosed with lung cancer on 10/4/83. Adriamycin was started (10/14/83) and discontinued (12/2/83) due to cardiotoxicity. Cardiac function deteriorated to Class IV congestive heart failure (CHF). The patient was placed on CoQ10 for her heart failure (1/22/84), and remained on CoQ10 for 30 months, during which CHF resolved to Class II and the cancer appeared to be in remission (pg.244, para.6).
A 63 year-old male with Class II congestive heart failure was diagnosed with cancer of the prostate (6/5/88). CoQ10 was started (7/6/88) to protect the heart during chemotherapy. A full course of chemotherapy was completed without increasing heart failure and with tumor suppression. CoQ10 therapy was stopped on 8/1/89 and 64 days later the patient was hospitalized with increasing heart failure and positive blood test for prostate cancer. CoQ10 therapy was resumed until 4/4/92 (17 months). The heart failure resolved to Class I and the cancer was in remission (pg.244, para.7).
Voulgaris discloses that intralesional administration of doxorubicin appears to be a safe and effective treatment and should be further explored in the management of brain gliomas resistant to conventional forms of treatment (abstract).
As discussed above, Knox’s treatment method, which is particularly useful in the treatment of tumors which have proven in a particular patient to be resistant to cancer therapy (e.g., chemotherapy), as evidenced by, for example, relapse, recurrence, or non-responsiveness to prior cancer therapy (reading on the subject having a failed treatment for the cancer with at least one chemotherapeutic regimen), involves administering an iSe compound in conjunction (e.g. prior to) the administration of a second cancer therapy, such as a cancer chemotherapeutic drug. In light of Narain’s disclosure of CoQ10’s use in treating oncological disorders in humans, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to combine the teachings of Knox with the teachings of Narain and intravenously administer Narain’s CoQ10 and/or pharmaceutical compositions thereof as the second cancer therapy in Knox’s treatment methods in an amount sufficient to kill all the tumor cells, shrink the tumor, or control the tumor growth (e.g. so as to maintain the tumor at its size at the initiation of therapy), by decreasing or delaying tumor growth. One of ordinary skill in the art would have been motivated to do so as Narain and Folkers evidence that CoQ10 has shown to be useful in treating cancer (e.g. Folkers discloses cases of remission after being on CoQ10 therapy) and increasing the survival rate of those with cancer. One of ordinary skill in the art would have had a reasonable expectation of success in doing so as Knox explicitly discloses CoQ10 as a suitable agent to use as the second cancer therapy in their methods, and Narain discloses that use of CoQ10 to reduce tumor size, inhibit tumor growth, and/or prolong the survival time of a tumor-bearing subject. Furthermore, Folkers discloses evidence that cancer patients being administered CoQ10 have shown to be in remission. Absent evidence to the contrary, it would be reasonable to interpret remission as reading on complete response or disappearance of all target lesions as remission indicates that all signs of cancer are gone (i.e. tumor has been eliminated).
Further, with regards to claims 61 and 62, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to administer Narain’s CoQ10 with a chemotherapeutic agent such as doxorubicin, when performing the method of the combined teachings of Knox and Narain discussed above. One of ordinary skill in the art would have been motivated to do so in order to optimize the anticancer effects of the treatment while also mitigating the toxic effects side effects of the chemotherapeutic agent. One of ordinary skill in the art would have had a reasonable expectation of success in doing so as Knox discloses that the second cancer therapy component of their method can involve chemotherapeutic agents such as doxorubicin; Narain discloses that chemotherapeutic agents such as doxorubicin may be used in conjunction with the CoQ10; Voulgaris discloses that doxorubicin appears to be an effective treatment and should be further explored in the management of brain gliomas; and Thornthwaite discloses that anthracyclines, such as doxorubicin, are among the most effective chemotherapeutic against in the treatment of numerous malignancies, and administering doxorubicin with CoQ10 was found to not interfere with the antineoplastic action of anthracyclines and might even enhance its anticancer effects. Thornthwaite and Narain also discloses that CoQ10 can also mitigate the toxic side effects of a chemotherapeutic agent.
Further, with regards to the dosages recited in the instant claim 30, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to try intravenously administering the CoQ10 at a dose of 50 mg/kg as Narain discloses that such a dose was shown to demonstrate higher survival rate. Furthermore, the dosage of CoQ10 is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. As discussed above, Narain discloses that those receiving higher doses of CoQ10 had a higher survival rate, and discloses one skilled in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of CoQ10 would be for the purpose of treating malignancies, based on factors such as the disease stage, age, sex, medical complications, and weight of the subject. Thus, it would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. In particular, it would have been obvious to one of ordinary skill in the art to engage in routine experimentation to determine the optimal CoQ10 dosage to administer based Narain’s disclosed intravenous CoQ10 dosages, and optimizing based on the aforementioned factors disclosed by Narain (e.g. stage of disease). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Furthermore, with regards to the instant claim 24, the frequency of the dosages of CoQ10 administered is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. As discussed above, Narain discloses that CoQ10 may be administered topically one or more times per 24 hours for six weeks or more. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. In particular, it would have been obvious to one of ordinary skill in the art to engage in routine experimentation to determine the optimal administration frequency of CoQ10 based on art recognized factors such as the type of administration (e.g., topical, injection, etc.), the stage of the tumor being treated, the subject’s responsiveness to the treatment, any side effects seen, etc. until the optimal result is seen, such as remission of the cancer. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention.
Claims 1, 8, 15, 17, 22-24, 30, 48, 49, 52, 61, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Narain et al. (Narain) (US 2011/0027247 A1; of record), Folkers et al. (Folkers) (Biochemical and Biophysical Research Communications; of record), Thornthwaite (US 2010/0209497 A1; of record), and Voulgaris et al. (Voulgaris) (Am J Clin Oncol; published 2002).
Narain discloses methods of treating an oncological disorder in a human, comprising administering Coenzyme Q10 (CoQ10) to the human in an amount sufficient to treat the oncological disorder, thereby treating the oncological disorder (abstract; para.0174). The CoQ10 is used to treat solid tumors (para.0180). Examples of cancers amenable to treatment with CoQ10 include, but are not limited to, cancer of the brain, head and neck, prostate, breast, testicular, pancreas, liver, colon, bladder, kidney, lung, non-small cell lung, melanoma, mesothelioma, uterus, cervix, ovary, sarcoma, bone, stomach, and Medulloblastoma (para.0180).
Narain defines “oncological disorder” to be interchangeable with “tumor” and “cancer” and refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. The definition includes metastasized cancer cells (para.0176) (reading on Stage IV tumor).
The CoQ10 can be administered by a variety of methods known in the art. Among the preferred route/mode of administration is by intravenous injection (para.0203). The composition may be in the form of liquid solutions (e.g., injectable solutions) (para.0202). Typically, the pharmaceutical composition comprises CoQ10 and a pharmaceutically acceptable carrier, such as water (para.0201). The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structures suitable to high drug concentration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients. In the case of sterile, lyophilized powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants, such as poloxamers (para.0204, 0235).
For injection, the compounds of the invention can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Ringer’s solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included (para.0205, 0221). The compositions may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents (para.0208). Narain exemplifies liposome dispersions of CoQ10 having an average particle diameter size of about 107 nm (para.0485, 0486), thus reading on CoQ10 being formulated as a nanodispersion.
In an embodiment, the CoQ10 may be topically administered to the human such that treatment occurs, wherein the CoQ10 is topically applied one or more times per 24 hours for six weeks or more (para.0240) (reading on the CoQ10 compound being administered at least one time per week).
The CoQ10 and/or pharmaceutical compositions thereof can be used in combination therapy with at least one other therapeutic agent. The CoQ10 and/or a pharmaceutical composition thereof is administered concurrently, prior to, or subsequent to administration of another therapeutic agent (para.0250, 0278). In an embodiment, the additional agent for use in the therapeutic method is a chemotherapeutic agent. Among the suitable chemotherapeutic agents include doxorubicin (para.0251, 0252).
Narain demonstrates the in vivo effects of CoQ10 administration on pancreatic cancer in their Example 45. An intravenously administered formulation of CoQ10 was evaluated for treating pancreatic cancer in an animal model. Rats with induced pancreatic cancer were randomized into groups and received one of 9 treatments. Narain found that after 28 days, all animals in Groups A (control) and B (saline solution) and the majority of the animals in Group C (vehicle) had died. In contrast, most of the animals in Groups D (5 mg/kg CoQ10), E (10 mg/kg CoQ10), and F (25 mg/kg CoQ10) remained alive, with those animals receiving the higher dose of CoQ10 remaining alive longer. All of the animals receiving the highest dose of CoQ10 (Group G: 50 mg/kg CoQ10) remained alive at 28 days. Narain discloses that these data demonstrate an overall dose response curve in which those animals receiving higher doses had a higher survival rate (para.0777-0787).
To evaluate the effectiveness of CoQ10 in treating pancreatic cancer in combination with doxorubicin, Group H was administered doxorubicin alone, while Group I was administered the combination of Doxorubicin and CoQ10. After 28 days, a significant number of the animals in Group H (5 mg/kg doxorubicin) had died due to the toxicity of doxorubicin, while those animals in Group I (50 mg/kg CoQ10 and 5 mg/kg doxorubicin) had an increased survival rate. Narain discloses that these data suggest that, in addition to increasing the survival rate associated with pancreatic cancer, CoQ10 can also mitigate the toxic side effects of a chemotherapeutic agent (para.0787).
Narain discloses that in an embodiment, the CoQ10 reduces tumor size, inhibits tumor growth (reading on stable disease), and/or prolongs the survival time of a tumor-bearing subject. Narain also discloses that their invention relates to a method of treating tumors in a human or other animal by administering to such human or animal an effective, nontoxic amount of CoQ10. Narain discloses that one skilled in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of CoQ10 would be for the purpose of treating malignancies. For example, a therapeutically effective amount of CoQ10 may vary according to factors such as the disease stage (e.g., stage I vs. stage IV), age, sex, medical complications (e.g., immunosuppressed conditions or disease), and weight of the subject, and the ability of the CoQ10 to elicit a desired response in the subject. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation (pra.0190).
With regards to the instant claim 15, while Narain does not appear to explicitly disclose treating a Stage III tumor, as discussed above, Narain discloses that one of ordinary skill in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of CoQ10 would be for the purpose of treating malignancies, noting that a therapeutically effective amount of CoQ10 may vary according to factors such as disease stage (e.g., stage I vs. stage IV). In light of this disclosure, Narain fairly suggests treating cancers across the spectrum between stage I and stage IV, adjusting the dosage by routine experimentation.
Further, with regards to the dosages recited in the instant claim 30, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to try intravenously administering the CoQ10 at a dose of 50 mg/kg as Narain discloses that such a dose was shown to demonstrate higher survival rate. Furthermore, the dosage of CoQ10 is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. As discussed above, Narain discloses that those receiving higher doses of CoQ10 had a higher survival rate, and discloses one skilled in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of CoQ10 would be for the purpose of treating malignancies, based on factors such as the disease stage, age, sex, medical complications, and weight of the subject. Thus, it would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. In particular, it would have been obvious to one of ordinary skill in the art to engage in routine experimentation to determine the optimal CoQ10 dosage to administer based Narain’s disclosed intravenous CoQ10 dosages, and optimizing based on the aforementioned factors disclosed by Narain (e.g. stage of disease). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Furthermore, with regards to the instant claim 24, the frequency of the dosages of CoQ10 administered is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. As discussed above, Narain discloses that CoQ10 may be administered topically one or more times per 24 hours for six weeks or more. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. In particular, it would have been obvious to one of ordinary skill in the art to engage in routine experimentation to determine the optimal administration frequency of CoQ10 based on art recognized factors such as the type of administration (e.g., topical, injection, etc.), the stage of the tumor being treated, the subject’s responsiveness to the treatment, any side effects seen, etc. until the optimal result is seen, such as remission of the cancer. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Narain does not appear to explicitly disclose applying their method to a subject has failed treatment for the solid tumor with at least one chemotherapeutic regimen. Folkers, Thornthwaite, and Voulgaris are relied upon for this disclosure. The teachings of Folkers, Thornthwaite, and Voulgaris are set forth above and incorporated herein.
As discussed above, Voulgaris discloses that doxorubicin appears to be an effective treatment and should be further explored in the management of brain gliomas, and Thornthwaite discloses that anthracyclines, such as doxorubicin, are among the most effective chemotherapeutic agents in the treatment of numerous malignancies, but their use is limited by a dose-dependent cardiotoxicity. Folkers also disclose case studies where cancer patients started on doxorubicin had to discontinue such treatment due to cardiotoxicity. In light of Narain’s, Thornthwaite’s, and Folkers’s disclosure that CoQ10 mitigates the toxic side effects a chemotherapeutic agent (e.g. doxorubicin’s cardiotoxicity), one of ordinary skill in the art would have found it prima facie obvious before the effective filing date to intravenously administer Narain’s CoQ10 and/or pharmaceutical compositions thereof to patients who had a previous failure with a doxorubicin treatment due to dose limiting cardiotoxicity. One of ordinary skill in the art would have been motivated to do so in order to widen the scope of patients able to benefit from Narain’s treatment and to mitigate the toxic side effects of the chemotherapeutic agent. One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Narain and Thornthwaite disclose that CoQ10 mitigates the toxic side effects of a chemotherapeutic agent, such as doxorubicin, and Folkers discloses that patients who had to discontinue doxorubicin significantly improved cardiac function after cardiotoxicity from doxorubicin when administered CoQ10, and the cancer appeared to be in remission.
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention.
Response to Arguments
Applicant's arguments filed May 23, 2025 have been fully considered but they are not persuasive.
(1) Applicant argues that post-filing studies confirmed that Coenzyme Q10 is effective in inhibiting tumor cell growth in brain cancer cells that have failed treatment with a chemotherapeutic agent. Applicant argues that the Narain Declaration shows that Coenzyme Q10 was effective in inhibiting tumor cell growth even in brain cancer (glioma) cell lines that are resistant to the chemotherapeutic agent temozolomide (TMZ) and demonstrate that Coenzyme Q10 restored sensitivity to a chemotherapeutic agent (TMZ) in brain cancer cells that were resistant to the chemotherapeutic agent.
Applicant argues that the ability of Coenzyme Q10 to restore sensitivity to the chemotherapeutic agent in brain cells would not have expected from the combined teachings of Knox, Narain, Folkers, and Thornthwaite. In particular, Applicant argues that Knox fails to teach or suggest that Coenzyme Q10 plays any role in sensitizing cancer cells to other chemotherapeutic agents. Applicant argues that Knox discloses that the second cancer therapy (e.g., Coenzyme Q10) is administered after the iSe compound has induced alteration of the tumor cell redox state, and therefore, the ability of Coenzyme Q10 to sensitize brain cancer cells to a chemotherapeutic agent to which they were previously resistant would not have been expected from the teachings of Knox.
Applicant further argues that Narain, Folkers, and Thornthwaite fail to disclose the claimed patient population (i.e., a subject that has failed treatment for the cancer with at least one chemotherapeutic regimen), the ability of Coenzyme Q10 to sensitize brain cancer cells to a chemotherapeutic agent to which they were previously resistant.
With regards to Applicant’s argument (1), the traversal argument is not found persuasive. With regards to Applicant’s argument that the ability of Coenzyme Q10 to sensitive brain cancer cells to a therapeutic agent to which they were previously resistant would not have been expected from the teachings of Knox, it is not necessarily required that that the prior art recognize a particular property or rationale. Note MPEP 2144(IV): “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).”
The claims as currently written do not preclude administration of additional agents prior to administration of Coenzyme Q10. The instant claims recite the transitional phrase “comprising” with regards to the administration step. The transitional term “comprising” is open-ended and does not exclude additional, unrecited elements or method steps. Note: MPEP 2111.03. Thus, the inclusion of additional steps, e.g., administration of Knox’s iSe compound prior to the administration of the second cancer therapy (e.g., CoQ10) would not be excluded from the instant claims.
As discussed above in detail, Knox’s treatment method, which is particularly useful in the treatment of tumors which have proven in a particular patient to be resistant to cancer therapy (e.g., chemotherapy), as evidenced by, for example, relapse, recurrence, or non-responsiveness to prior cancer therapy (reading on the subject having a failed treatment for the cancer with at least one chemotherapeutic regimen), involves administering an iSe compound in conjunction (e.g. prior to) the administration of a second cancer therapy, such as a cancer chemotherapeutic drug. In light of Narain’s disclosure of CoQ10’s use in treating oncological disorders in humans (e.g., brain cancer), one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to combine the teachings of Knox with the teachings of Narain and intravenously administer Narain’s CoQ10 and/or pharmaceutical compositions thereof as the second cancer therapy in Knox’s treatment methods in an amount sufficient to kill all the tumor cells, shrink the tumor, or control the tumor growth (e.g. so as to maintain the tumor at its size at the initiation of therapy), by decreasing or delaying tumor growth. One of ordinary skill in the art would have been motivated to do so as Narain and Folkers evidence that CoQ10 has shown to be useful in treating cancer (e.g. Folkers discloses cases of remission after being on CoQ10 therapy) and increasing the survival rate of those with cancer. One of ordinary skill in the art would have had a reasonable expectation of success in doing so as Knox explicitly discloses CoQ10 as a suitable agent to use as the second cancer therapy in their methods, and Narain discloses that use of CoQ10 to reduce tumor size, inhibit tumor growth, and/or prolong the survival time of a tumor-bearing subject. Furthermore, Folkers discloses evidence that cancer patients being administered CoQ10 have shown to be in remission. Absent evidence to the contrary, it would be reasonable to interpret remission as reading on complete response or disappearance of all target lesions as remission indicates that all signs of cancer are gone (i.e. tumor has been eliminated).
While the combined teachings of Knox, Narain, Folkers, and Thornthwaite discloses the administration of iSe prior to the administration of the second cancer therapy (e.g., CoQ10) as the iSe compound provides for sensitization of tumor cells to cancer therapy, as discussed above, the inclusion of additional steps, e.g., administration of Knox’s iSe compound prior to the administration of the second cancer therapy (e.g., CoQ10) would not be excluded from the instant claims because the instant claims recite the open transitional phrase, “comprising.”
With regards to the combined teachings of Narain, Folkers, and Thornthwaite, in light of Narain’s, Thornthwaite’s, and Folkers’s disclosure that CoQ10 mitigates the toxic side effects a chemotherapeutic agent (e.g. doxorubicin’s cardiotoxicity), one of ordinary skill in the art would have found it prima facie obvious before the effective filing date to intravenously administer Narain’s CoQ10 and/or pharmaceutical compositions thereof to patients who had a previous failure with a doxorubicin treatment due to dose limiting cardiotoxicity. One of ordinary skill in the art would have been motivated to do so in order to widen the scope of patients able to benefit from Narain’s treatment and to mitigate the toxic side effects of the chemotherapeutic agent. One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Narain and Thornthwaite disclose that CoQ10 mitigates the toxic side effects of a chemotherapeutic agent, such as doxorubicin, and Folkers discloses that patients who had to discontinue doxorubicin significantly improved cardiac function after cardiotoxicity from doxorubicin when administered CoQ10, and the cancer appeared to be in remission.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8, 15, 17, 22-24, 30, 48, 49, 52, 61, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over (i) claims 1-19 of U.S. Patent No. 8,562,976 B2 (USPN 976), (ii) claims 1-13 of U.S. Patent No. 8,771,680 B2 (USPN 680), (iii) claims 1-32 of U.S. Patent No. 10,933,032 B2 (USPN 032), (iv) claims 1-53 of U.S. Patent No. 9,901,542 B2 (USPN 542), and (v) claims 1-36 of U.S. Patent No. 11,298,313 B2 (USPN 313), each in view of Narain et al. (Narain) (US 2011/0027247 A1; of record), Folkers et al. (Folkers) (Biochemical and Biophysical Research Communications; of record), and Thornthwaite (US 2010/0209497 A1; of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims claim substantially similar and overlapping methods of treating cancer (oncological disorder), in a subject (e.g., human) by administration of Coenzyme Q10 (CoQ10). The pr