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
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/12/2024 has been entered.
Claim Status
Claims 1-27, 30, and 32-37 are pending.
Applicant previously elected the species of (i) hydrochloric acid, (ii) venetoclax (ABT-199), (iii) CART123, (iv) Myelodysplastic Syndrome (MDS), and (v) an elderly human, in the reply filed on 8/21/2022. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The following species have been rejoined for prosecution: (iv) acute myeloid leukemia (AML). Instant claims 25-26 have been rejoined.
Claims 5, 8-16, 18-20, and 27 remain withdrawn.
Claims 1-4, 6-7, 17, 21-26, 30, 32-37 are pending and read on the species under examination.
Rejections Withdrawn
The rejections of claims 28-29 and 31 are moot in view of claim cancelation.
The rejections of claims 1-4, 6-7, 17, 21-24, 30, and 32-37 under 35 USC § 103 are withdrawn in view of claim amendment.
The rejections of claims 1-4, 6-7, 17, 21-24, 30, and 32-37 under nonstatutory double patenting are withdrawn in view of claim amendment.
Claim Objections Necessitated by Amendment
Claims 1-4 ,6-7, 17, 21-26, 30, and 32-37 are objected to because of the following informalities: in the second to the last line of instant claims 1 and 36-37, a “human who are weakened” is claimed which is grammatically incorrect rather than a ---human who is weakened---.
Instant claims 2-4 ,6-7, 17, 21-26, 30 and 32-35 are dependent on instant claims 1 and 36-37 without narrowing the subject matter outside of the objection.
Appropriate correction is required.
Claim Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 30 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 30, the metes and bounds of the method are unclear because the claim is dependent on a canceled claim.
To promote compact prosecution the claim will be interpreted as dependent on claim 1.
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.
Claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007) and evidenced by Zuckerman T et al. (Blood (2015) 126 (23): 3810).
Gengrinovitch taught the use of prodrugs to impart desired characteristics such as increased bioavailability is a recognized concept in the art of pharmaceutical development (page 2, paragraph 17).
Regarding instant claims 1 and 36-37, Gengrinovitch provides a compound having the general formula (I):
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(page 2, paragraph 17) and a method of treating cancer by administering to a subject in need thereof a therapeutically effective amount of the compound (page 4, paragraph 63). Gengrinovitch taught a method of increasing the uptake of an anti-proliferative agent by neoplastic cells comprising contacting the neoplastic cells with an anti-proliferative compound of Formula I (page 4, paragraph 63).
Regarding instant claims 1 and 36-37, Gengrinovitch explicitly teaches a cytarabine conjugated prodrug embraced by instant formula (I) (page 19, claim 7).
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Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a drug or prodrug in which the drug undergoes rapid uptake by cancer cells (page 2, paragraph 28). Gengrinovitch taught the compounds have utility in the delivery of active agents to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent (page 7, paragraph 129). Gengrinovitch taught delivery can be improved by delivering more active agent over a period of time, or in delivering active agent in a particular time period (such as to effect quicker or delayed delivery) or over a period of time (such as sustained delivery) (page 7, paragraph 129).
Regarding instant claims 23-26, Gengrinovitch teaches that the conjugate(s) may be employed in the treatment of non-solid tumors including lymphoproliferative disorders including leukemias and lymphomas (page 4, paragraph 57) for a human (page 4, paragraph 59). Regarding instant claim 30, Gengrinovitch provides a method of overcoming multi-drug resistance in neoplastic cells comprising contacting the neoplastic cells with an anti-proliferative compound selected from a compound having general formula (I) (page 4, paragraph 64).
Regarding instant claims 32-33, Gengrinovitch teaches intravenous administration of the composition (page 4, paragraph 70), which also meets the limitation of a parenteral administration.
Regarding instant claims 1 and 36-37, Gengrinovitch teaches administration of pharmaceutical compositions comprising compounds having general formula (1) and a pharmacologically acceptable excipient (page 4, paragraph 55).
Regarding instant claims 4 and 6, Gengrinovitch teaches administration of pharmaceutical compositions comprising pharmaceutically acceptable salts of the compounds of general formula (I). A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt (page 7, paragraph 125).
Gengrinovitch does not teach:
administering a second pharmaceutical composition comprising a therapeutically effective amount of at least one additional anti-neoplastic agent, wherein the first and second pharmaceutical compositions are administered to the subject concurrently or sequentially, thereby reducing cancer cell proliferation in the subject;
the anti-neoplastic agent is bound or attached to immune cells capable of inhibiting cancer cell growth, wherein the immune cells are chimeric antigen receptor T cells (CART), wherein the CART is CART123;
that the at least one anti-neoplastic agent is venetoclax;
the hematological cancer is specifically acute myeloid leukemia; and
treatment of a medically compromised human who is weakened or impaired medically,
but these deficiencies are obvious in view of PracticeUpdate, Deng and Lin.
Regarding instant claims 1 and 36-37, PracticeUpdate taught astarabine, a prodrug of cytarabine – which has an identical structure to instant formula (I) –, appears safe and well tolerated, including in patients over 80 years of age, and resulted in complete remission in three of nine patients with acute leukemia (page 1, lines 1-2). PracticeUpdate taught cytarabine cannot be used in patients with renal failure due to these patients’ decreased elimination and increased blood levels, which raise toxicity (page 1, line 14). PracticeUpdate taught when astarabine enters the cell, cytarabine is cleaved from the amino acid and is ready to interfere with DNA synthesis and cause cell death (page 1, line 17). Regarding instant claims 1 and 36-37, PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: 1) spares other tissues and thus can be given to patients with comorbidities; and 2) can be delivered in higher doses with an anticipated better antileukemic effect (page 1, lines 18-20). PracticeUpdate taught treatment with astarabine in clinical trials showed the first three cohorts of medically unfit patients had encouraging responses with complete responses and minimal side effects, wherein the patients had relapsed/refractory leukemia (page 1, lines 21-23). PracticeUpdate taught four patients of nine patients with relapsed/refractory leukemia were alive after a follow-up period of 1-10 months, wherein two were in continuous complete response 6 months after treatment (page 2, lines 3-6).
Regarding instant claims 23-26, Zuckerman evidenced one patient with a complete response above had acute myeloid leukemia and was 81 years old (Zuckerman, Table 1, patient no. 5). Regarding instant claims 1 and 36-37, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies directed against specific disease-associated mutations (such as sorafenib against FLT3 internal tandem duplication) and/or maintenance therapy using hypomethylating agents will prolong remission duration (page 2, lines 13-15).
Regarding instant claims 1, 21-22, and 36-37, Deng teaches combination cytarabine-induced AML cell apoptosis was enhanced by cytotoxic T lymphocytes (CTL) treatment. Bcl-2 expression was downregulated in AML cells following cytarabine and CTL treatment, indicating that the synergistic effect of this treatment on AML cell apoptosis is due to the downregulation of Bcl-2 (Abstract).
Regarding instant claims 1, 21-22, and 36-37, Deng taught concurrent treatment of CTL and cytarabine for increasing cancer cell apoptosis (cell death)(Figure 2).
Deng further teaches there are several limitations to CTLs treatment, including shortcomings in specificity and cytotoxic competence. Regarding instant claims 1, 21-22, and 36-37, Deng taught the specific targeting of immunotherapy could improve these issues; for example, chimeric antigen receptor-modified T cell (CAR-T) treatment. CART-123 cells, which target the CD123 antigen on tumor cells, have achieved favorable results whereby CD123 CAR T cells exhibited antileukemic activity in vivo against a xenogeneic model of AML and significantly prolonged the models' survival. CAR-T treatments are able to reduce tumor burden prior to the application of alternative intensive strategies, including HSCT (Discussion).
Regarding instant claims 1-3, 7, 17, 23-26, 30, and 36-37, Lin taught combination therapy of venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy when combined with cytarabine in several AML cell lines and primary samples (abstract). Lin taught treatment options for older patients with AML unfit for intensive chemotherapy are limited with complete remission rates for low-dose cytarabine of about 10% (abstract). Regarding instant claims 1-3, 7, 17, 23-26, 30, and 36-37, Lin taught in a phase 1/2 dose-escalation/expansion study of venetoclax + low dose cytarabine, in treatment-naïve AML pts ≥ 65 years not eligible for intensive chemotherapy the overall response rate in phase 1 was 44% (complete remission, n = 4; complete remission without complete marrow recovery, n = 4) (abstract). Lin taught no clinically significant tumor lysis syndrome was observed (abstract).
Regarding instant claims 1-3, 7, 17, 21-26, 30, 32-33, and 37, it would have been obvious to a person having ordinary skill in the art to modify the method of treating human leukemia with the cytarabine containing prodrug compound with the structure
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and a pharmaceutically acceptable salt form intravenously as taught by Gengrinovitch to further comprise: 1) concurrent combination CAR T Cell therapy with CART-123 cells as taught by Deng; 2) concurrent combination treatment with ABT-199 (venetoclax) as taught by Lin; 3) treatment of older patients with AML with relapsed/refractory disease as taught by PracticeUpdate; and 4) treatment wherein the subject is medically compromised who is weakened or impaired medically as taught by PracticeUpdate.
This would produce a method of treating a human subject with relapsed or refractory (instant claim 30) AML (instant claims 25-26), which is a hematological leukemia (instant claims 23-24), by: a) administering a therapeutically effective amount of the anti-proliferative cytarabine prodrug with the structure:
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with a pharmaceutically acceptable excipient, intravenously (claim 33)(which is a form of parenteral administration (claim 32) and b) administering a second pharmaceutical composition of the Bcl-2 inhibitor ABT-199 (venetoclax)(claim 7 and 17) and CART-123 cells (claim 22)(which have the anti-neoplastic CD123 targeting agent bound to the CART cell (claim 21)) in combination concurrently (claims 2-3) and, thereby reducing cancer cell proliferation, wherein the subject is medically compromised who is weakened or impaired medically (claim 1 and 37). Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is obvious because: 1) Deng’s teachings that cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) Lin taught combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44%; 3) PracticeUpdate taught astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; and 4) PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration. One of ordinary skill in the arts would have been motivated, with a reasonable expectation of success, that treating AML via a method of administering Bcl-2 inhibitors would be an effective treatment for AML.
There is a reasonable expectation of success because Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent and explicitly taught the structure of the cytarabine prodrug and: 1) cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44% in humans; 3) astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; and 4) astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
Further, in regards to instant claims 1-3, as administrations of the two compositions may only be done concomitantly or sequentially, the limitations regarding the sequence of administrations are met.
In regards to instant claim 36, as the method of administering a compound represented by the structure of formula (1) and a Bcl-2 inhibitor concurrently to a relapsed or refractory AML patient wherein the subject is medically compromised who is weakened or impaired medically is taught by the prior art as discussed above, the limitation of “wherein the administering results in a reduction in side effects in the subject, wherein the side effects comprise at least one of mucositis, diarrhea, or alopecia, relative to side effects observed in subjects treated with cytarabine and the at least one additional anti-neoplastic agent or a second pharmaceutical composition comprising cytarabine and the at least one additional anti-neoplastic agent” would necessarily follow. Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues generally, when two compounds act together, their combination effect can be categorized into three main types: additive, if the effect of the combination is equivalent to the sum of the effects of two compounds acting individually, synergistic, if the combination effect is greater than additive, and antagonistic, if the combination effect is less than additive.
As argued in the previous responses to the Office Actions, designing effective therapies for cancer treatment, and combinations for cancer treatments are important but challenging tasks. The preferred combination effect is, of course, the synergistic effect. Unfortunately, the presence of a synergistic effect between two drugs can vary, depending on a large number of factors, besides the drugs themselves and their mode of action. As important factors influencing the presence of a synergistic effect are the pharmacokinetic and pharmacodynamic properties of the drugs, in Vitro studies may not always be capable of predicting the complexities of drug interactions within the human body.
As presented in previous responses to Office Actions, the compound of formula (1) is not cytarabine and thus none of the specific effects previously shown for cytarabine could be anticipated for a compound of formula (1 ). The Applicant argues that although compound of formula (1) is a pro-drug of cytarabine and eventually, as a result, exerts the same biological activity - the two compounds have different properties that affect their clinical outcome.
Compound of formula (1) and cytarabine due to their difference in structure, differ in their plasma pharmacokinetic (PK) properties and kinetics of entry into the cells. These differences affect the safety and efficacy both as single agents and in combination with other therapeutics.
Therefore, the different properties of compound of formula (1) and cytarabine, denies a person of skilled in the art to extrapolate the pharmacological effect of cytarabine to compound of formula (1).
Drugs can interact with each other such that the bioavailability of one drug is increased or prolonged (pharmacokinetic interaction) or the target receptor or pathway is modulated to elicit a stronger therapeutic response (pharmacodynamic interaction). The mere fact that a specific drug can have a synergistic effect with cytarabine, cannot imply of the interaction this drug would have with compound of formula (1 ), as the two compounds are different and have different properties. Indeed, as presented in the previous responses to the Office Actions, those differences also cause different clinical performance.
Moreover, amended claim 1 also recites "wherein said subject is a medically
compromised human". This is another surprising and unexpected characteristic of the
treatment, that arises from the fact the compound of formula (1) is not cytarabine and therefore causes a different clinical effect. The Examiner does not argue that the above publications teach or suggest treating a medically compromised human patient.
The use of Cytarabine and/or its conjugates is often limited by high toxicity and not sufficient efficacy due to poor cellular uptake, low conversion to the active triphosphate metabolite, rapid deactivation or clearance and development of resistance mechanisms.
The recommended daily dosages of cytarabine approved by the U.S. FDA for
administration to a human subject, which dosage does not cause unacceptable adverse effects and is dependent on the subject's age and physical condition so that a subject of 50 or less years of age can be typically treated with a daily dose of cytarabine of up to 3 g/m2, a subject of 50 to 60 years of age can be typically treated with a daily dose of cytarabine of up to 1.5 g/m2, a subject of 60 to 7 5 years of age can be typically treated with a daily dose of cytarabine ranging from 0.1 g/m2 to 0.5 g/m2, and a subject of 75 or more years of age can be treated with a daily dose of cytarabine of up to 20 mg/m2 of the subject's surface area. However, it should be noted that most of the subjects of 75 or more years of age cannot be treated with cytarabine at all due to its severe adverse effects.
Intensive induction chemotherapy is the standard of care for first-line treatment of
AML. Cytarabine is part of the standard approach, but many older adults and those with
significant comorbidities have difficulty tolerating it.
The maximal standard of care dose of cytarabine is decreased as the age goes up and in medically compromised patients. Therefore, the fact that the claimed combination can be administered to medically compromised patients is novel and surprising.
Applicant indicates in order to expedite allowance, claims 1, 36 and 37 have been amended to recite "and wherein said subject is a medically compromised human who are weakened or impaired medically", rendering the rejections moot.
In response, Applicants arguments dated 8/12/2024 have been considered but are not found to be persuasive.
As indicated above, PracticeUpdate taught combination therapy using astarabine – which has an identical structure to instant formula (I) – combined with other targeted therapies directed against specific disease-associated mutations (such as sorafenib against FLT3 internal tandem duplication) and/or maintenance therapy using hypomethylating agents will prolong remission duration. PracticeUpdate taught astarabine, a prodrug of cytarabine – which has an identical structure to instant formula (I) –, appears safe and well tolerated, including in patients over 80 years of age, and resulted in complete remission in three of nine patients with acute leukemia and as effective in relapsed/refractory AML. PracticeUpdate recognized astarabine acts as a targeted therapy in leukemia which: 1) spares other tissues and thus can be given to patients with comorbidities; and 2) can be delivered in higher doses with a better antileukemic effect. PracticeUpdate taught treatment with astarabine in clinical trials showed the first three cohorts of medically unfit patients had encouraging responses with complete responses and minimal side effects, wherein the patients had relapsed/refractory leukemia. Thus, the prodrug capabilities of the structure of instant formula (I) for treatment of medically unfit human populations were previously known. Further, it was known that astarabine is efficacious when given to elderly human AML patients and those medically unfit for cytarabine treatment because astarabine spares other tissues. Thus, it is not surprising to give astarabine to this patient population because it was previously known to be effective.
Further, US 20110275590 (Gengrinovitch Set al., reference of record) explicitly taught the amino acid conjugate embraced by instant formula (1) (page 19, claim 7)( indicated as aspacytarabine in the instant application). Gengrinovitch further taught the conjugate serves as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells due to the amino acid derivative linked to the drug (specification, page 2, paragraph 28). Gengrinovitch taught the conjugates demonstrate enhanced uptake by proliferating cells such as neoplastic cells, yet exhibit limited uptake and reduced toxicity to normal cells (specification, page 4, paragraph 74). Gengrinovitch further recognized the concept of using prodrugs to impart desired characteristics such as increased bioavailability or increased site-specificity (specification, page 2, paragraph 17). Thus, the aspacytarabine prodrug of Gengrinovitch was already recognized to have more desirable pharmacokinetic properties and kinetics of entry into the cells (better bioavailability and more rapid absorption in cancer cells). Therefore, it is not unexpected that treatment with the aspacytarabine prodrug in combination: 1) would have greater safety ; and 2) higher efficacy, which translates to a better clinical outcome - when cancer cells uptake the drug more rapidly compared to normal cells.
Moreover, combination treatments that are known to be effective an provide synergy with cytarabine would also be effective with the cytarabine prodrug astarabine based on the known mechanism of action because it exerts the same biological activity.
Regarding combination with CART-123 cells, as taught above, Deng taught cytarabine has synergistic effects when combined with CTL and taught the specific targeting of immunotherapy could improve these issues; for example, chimeric antigen receptor-modified T cell (CAR-T) treatment. CART-123 cells, which target the CD123 antigen on tumor cells, have achieved favorable results whereby CD123 CAR T cells exhibited antileukemic activity in vivo against a xenogeneic model of AML and significantly prolonged the models' survival.
Regarding combination with venetoclax, , Lin taught combination therapy of venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy when combined with cytarabine in several AML cell lines and primary samples. Lin further taught in a phase 1/2 dose-escalation/expansion study of venetoclax + low dose cytarabine, in treatment-naïve AML pts ≥ 65 years not eligible for intensive chemotherapy the overall response rate in phase 1 was 44% with no clinically significant tumor lysis syndrome observed.
As indicated in the obvious rational above, combination of the structure of instant formula (I) with CART-123 or venetoclax is obvious with a reasonable expectation of success, absent surprising results.
The Applicant indicates Examiner further alleges in the Advisory Action, dated April 24, 2024, that the Applicant has not provided any unexpected results for the elected species combination if the structure of formula I (aspacytarabine) and venetoclax in MDS.
The Applicant respectfully disagrees, but in order to expedite allowance, claim 24 has been amended to delete the treatment of MDS, rendering the rejection moot.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Appendix I of Altman et al. (reference of record) indicates two separate AML cohorts were treated:
1) Cohort I was treated with 200 mg venetoclax in combination with 2.3 g/m2/day aspacytarabine and had a CR response rate of 1 CR in 4 patients or 25%.
2) Cohort II was treated with 400 mg venetoclax in combination with 2.3 g/m2/day aspacytarabine and had a CR response rate of 3 CR in 3 patients or 100%.
Thus, Cohort I of Altman et al. treated with 200 mg venetoclax in combination with 2.3 g/m2/day aspacytarabine has a response rate that is about the same as cytarabine in combination with venetoclax in Slater et al. (reference of record), 25% vs. 27%, respectively. Thus, CR response rate results for cohort I are unsurprising. Unexpected results are required to be commensurate in scope with claimed invention. MPEP 716.02(d) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range."
Claims 1-4, 6-7, 17, 21-26, 30, 32-33, and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007) as applied to claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 above, and further in view of Fasinu (Fasinu et al. Biopharmaceuticals & Drug Disposition (2011), Vol. 32, pages 185-209, reference of record).
The teachings of Gengrinovitch, PracticeUpdate, Deng and Lin are discussed supra.
Gengrinovitch, PracticeUpdate, Deng and Lin do not explicitly teach the pharmaceutically acceptable salt of the compound of formula (1) is a salt of hydrochloric acid.
This deficiency is addressed by Fasinu.
Regarding claims 4 and 6, Fasinu teaches that drug dosage forms and formulation design can be modified to improve oral bioavailability of drugs (page 188, left column, first paragraph). Regarding claims 4 and 6, Conventional approaches to enhancing the solubility properties and oral bioavailability of hydrophobic drugs include the synthesis of molecular species such as salts to facilitate dissolution, e.g. addition of hydrochloride, sulphate or phosphate moieties (page 188, left column, first bullet).
Regarding claims 4 and 6, in the absence of unexpected results, the formulation of an amino acid-cytarabine conjugate of Gengrinovitch into a pharmaceutically acceptable salt thereof using a known, conventional organic or inorganic acid useful for cytarabine (e.g, HCl or acetic acid) by known process; and the administration of pharmaceutically acceptable salt of an amino acid-cytarabine conjugate of Gengrinovitch for the treatment of AML would have been prima facie obvious to one of ordinary skill in the art at the time of the instant filing. All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Applicant’s Arguments
Applicant argues claims 4 and 6 are dependent from claim 1, therefore possess all its limitations. As argued above, claim 1 is novel and inventive, therefore claims 4 and 6 are likewise novel and inventive.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-3, 7, 17, 21-26, 30, 32-37 are rejected under 35 U.S.C. 103 as being unpatentable over Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007) as applied to claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 above, and further in view of Zuckerman T et al. (Blood (2015) 126 (23): 3810).
The teachings of Gengrinovitch, PracticeUpdate, Deng and Lin are discussed supra.
Gengrinovitch, PracticeUpdate, Deng and Lin are silent to administration of the compound of formula (1) to the subject at a dose of about 0.8 g/m2 to about 6 g/m2 of the subject's body surface area per day.
This deficiency is addressed by Zuckerman.
Regarding instant claims 34-35, Zuckerman taught astarabine, a pro-drug of cytarabine – with an identical structure to instant formula (I) –, is safe and very well tolerated, including patients over 80 years of age, and resulted in complete remission in 3 of 9 patients with acute leukemia (page 2, conclusions). Regarding instant claims 34-35, Zuckerman taught relapsed/refractory AML patients were dosed with 0.5 g/m2 to 4.5 g/m2 astarabine and the dosage was effective (abstract).
Regarding claims 34-35, one of ordinary skill in the arts would have been motivated to, with a reasonable expectation of success, administer the structure of instant formula (1) in relapsed/refractory AML because it is safe and very well tolerated, in patients with relapsed/refractory AML including in patients over 80 years of age, wherein treatment with dosages of 0.5 g/m2 to 4.5 g/m2 resulted in complete remission in 3 of 9 patients with acute leukemia.
Applicant’s Arguments
Applicant argues claims 34-35 are dependent from claim 1, therefore possess all its limitations. As argued above, claim 1 is novel and inventive, therefore claims 4 and 6 are likewise novel and inventive.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 6-7, 17, 21-26, 30, 32-33, and 36-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,104,698 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007).
Regarding instant claims 1, 4, 6, and 36-37, patented claim 8 taught a method of reducing cancer proliferation or treating a cancer in a subject afflicted with the cancer comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the structure of formula (1):
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, wherein the pharmaceutically acceptable salt is a salt of hydrochloric acid in patented claim 2.
Regarding instant claim 37, patented claim 7 taught the pharmaceutical compound comprises a pharmaceutically acceptable excipient.
Regarding instant claims 23-24, patented claim 12 and 18 taught the cancer is AML and MDS.
Regarding instant claims 1 and 36-37, patented claim 19 taught the subject is human.
The U.S. patent does not teach administering a second pharmaceutical composition comprising a therapeutically effective amount of at least one additional anti-neoplastic agent, wherein the first and second pharmaceutical compositions are administered to the subject concurrently or sequentially, thereby reducing cancer cell proliferation in the subject, and wherein said subject is a medically compromised human
who are weakened or impaired medically.
The U.S. patent does not teach that the at least one anti-neoplastic agent is venetoclax.
The U.S. patent does not teach the anti-neoplastic agent is bound or attached to immune cells capable of inhibiting cancer cell growth, wherein the immune cells are chimeric antigen receptor T cells (CART)
The U.S. patent does not teach the CART is CART123.
The U.S. patent does not explicitly teach the compound of formula (1) administered to the subject ranges from about 0.8 g/m2 to about 6 g/m2 of the subject's body surface area per day.
The U.S. patent does not explicitly teach the subject has relapsed or refractory AML.
These deficiencies are made up for by Gengrinovitch, PracticeUpdate, Deng, and Lin.
Gengrinovitch, PracticeUpdate, Deng, and Lin are described above.
Regarding instant claims 1-4, 6-7, 17, 21-26, 30, 32-33, and 37, it would have been obvious to a person having ordinary skill in the art to modify the method of patented claims 8, 19, and 23-24 for treating a human with AML with the cytarabine containing prodrug compound of the structure
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and a pharmaceutically acceptable HCl salt form – and to include: 1) concurrent combination CAR T Cell therapy with CART-123 cells as taught by Deng; 2) concurrent combination treatment with ABT-199 (venetoclax) as taught by Lin; 3) treatment of older patients with relapsed/refractory AML disease as taught by PracticeUpdate; 4) treatment wherein the subject is medically compromised who is weakened or impaired medically as taught by PracticeUpdate; and 5) intravenously administer the prodrug as taught by Gengrinovitch.
This would produce a method of treating a human subject with relapsed or refractory (instant claim 30) AML (instant claims 25-26), which is a hematological leukemia (instant claims 23-24), by: a) administering a therapeutically effective amount of the anti-proliferative cytarabine prodrug with the structure:
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of the HCl salt (instant claims 4 and 6) with a pharmaceutically acceptable excipient, intravenously (claim 33)(which is a form of parenteral administration (claim 32) and b) administering a second pharmaceutical composition of the Bcl-2 inhibitor ABT-199 (venetoclax)(claim 7 and 17) and CART-123 cells (claim 22)(which have the anti-neoplastic CD123 targeting agent bound to the CART cell (claim 21)) in combination concurrently (claims 2-3) and, thereby reducing cancer cell proliferation, wherein the subject is medically compromised who is weakened or impaired medically (claim 1 and 37). Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is obvious because: 1) Deng’s teachings that cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) Lin taught combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44%; 3) PracticeUpdate taught astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 4) PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 5) Gengrinovitch taught intravenous administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration. One of ordinary skill in the arts would have been motivated, with a reasonable expectation of success, that treating AML via a method of administering Bcl-2 inhibitors would be an effective treatment for AML.
There is a reasonable expectation of success because Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent and explicitly taught the structure of the cytarabine prodrug and: 1) cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44% in humans; 3) astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 4) astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 5) intravenous administration is a known effective route of administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
Further, in regards to instant claims 1-3, as administrations of the two compositions may only be done concomitantly or sequentially, the limitations regarding the sequence of administrations are met.
In regards to instant claim 36, as the method of administering a compound represented by the structure of formula (1) and a Bcl-2 inhibitor concurrently to a relapsed or refractory AML patient wherein the subject is medically compromised who is weakened or impaired medically is taught by the prior art as discussed above, the limitation of “wherein the administering results in a reduction in side effects in the subject, wherein the side effects comprise at least one of mucositis, diarrhea, or alopecia, relative to side effects observed in subjects treated with cytarabine and the at least one additional anti-neoplastic agent or a second pharmaceutical composition comprising cytarabine and the at least one additional anti-neoplastic agent” would necessarily follow. Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-4, 6-7, 17, 21-26, 30, and 32-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,104,698 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007), and Zuckerman T et al. (Blood (2015) 126 (23): 3810).
The claims of the ‘698 patent in view of Gengrinovitch, PracticeUpdate, Deng, and Lin teach the limitations of claims 1-4, 6-7, 17, 21-26, 30, 32-33, and 36-37 for the reasons set forth above.
‘698 does not teach administration of the compound of formula (1) to the subject at a dose of about 0.8 g/m2 to about 6 g/m2 of the subject's body surface area per day, but this is addressed by Zuckerman.
The teachings of’698, Gengrinovitch, PracticeUpdate, Deng, Lin, and Zuckerman are discussed supra.
Regarding instant claims 34-35, Zuckerman taught astarabine, a pro-drug of cytarabine – with an identical structure to instant formula (I) –, is safe and very well tolerated, including patients over 80 years of age, and resulted in complete remission in 3 of 9 patients with acute leukemia (page 2, conclusions). Regarding instant claims 34-35, Zuckerman taught relapsed/refractory AML patients were dosed with 0.5 g/m2 to 4.5 g/m2 astarabine and the dosage was effective (abstract).
Regarding claims 34-35, one of ordinary skill in the arts would have been motivated to, with a reasonable expectation of success, administer the structure of instant formula (1) in relapsed/refractory AML because it is safe and very well tolerated, in patients with relapsed/refractory AML including in patients over 80 years of age, wherein treatment with dosages of 0.5 g/m2 to 4.5 g/m2 resulted in complete remission in 3 of 9 patients with acute leukemia.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 8,993,278 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007).
Regarding instant claims 1, 21-23 and 36-37, patented claims 1 and 6 taught a method of treating a cancer in a subject afflicted with the cancer comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the structure of formula (1):
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Regarding instant claim 37, patented claims 1 and 9 taught the pharmaceutical compound comprises a pharmaceutically acceptable excipient.
Regarding instant claim 28, patented claims 1 and 9 taught the pharmaceutical composition is for human administration.
The U.S. patent does not teach administering a second pharmaceutical composition comprising a therapeutically effective amount of at least one additional anti-neoplastic agent, wherein the first and second pharmaceutical compositions are administered to the subject concurrently or sequentially, thereby reducing cancer cell proliferation in the subject.
The U.S. patent does not explicitly teach the pharmaceutically acceptable salt of the compound of formula (1) is a salt of hydrochloric acid.
The U.S. patent does not explicitly teach the compound of formula (1) administered to the subject ranges from about 0.8 g/m2 to about 6 g/m2 of the subject's body surface area per day.
The U.S. patent does not explicitly teach the subject is an elderly human is 70 or more years of age.
The U.S. patent does not teach treating AML or MDS.
The U.S. patent does not teach that the at least one anti-neoplastic agent is venetoclax.
The U.S. patent does not teach the anti-neoplastic agent is bound or attached to immune cells capable of inhibiting cancer cell growth, wherein the immune cells are chimeric antigen receptor T cells (CART)
The U.S. patent does not teach the CART is CART123.
These deficiencies are made up for by Gengrinovitch, PracticeUpdate, Deng, and Lin.
Gengrinovitch, PracticeUpdate, Deng, and Lin are described above.
Regarding instant claims 1-3, 7, 17, 21-26, 30, 32-33, and 37, it would have been obvious to a person having ordinary skill in the art to modify the method of patented claims 1, 6, and 9 for treating a human with cancer with the cytarabine containing prodrug compound of the structure
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and a pharmaceutically acceptable excipient – and to include: 1) concurrent combination CAR T Cell therapy with CART-123 cells as taught by Deng; 2) concurrent combination treatment with ABT-199 (venetoclax) as taught by Lin; 3) treatment of older patients with relapsed/refractory AML disease as taught by PracticeUpdate; 4) treatment wherein the subject is medically compromised who is weakened or impaired medically as taught by PracticeUpdate; and 5) intravenously administer the prodrug as taught by Gengrinovitch.
This would produce a method of treating a human subject with relapsed or refractory (instant claim 30) AML (instant claims 25-26), which is a hematological leukemia (instant claims 23-24), by: a) administering a therapeutically effective amount of the anti-proliferative cytarabine prodrug with the structure:
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with a pharmaceutically acceptable excipient, intravenously (claim 33)(which is a form of parenteral administration (claim 32) and b) administering a second pharmaceutical composition of the Bcl-2 inhibitor ABT-199 (venetoclax)(claim 7 and 17) and CART-123 cells (claim 22)(which have the anti-neoplastic CD123 targeting agent bound to the CART cell (claim 21)) in combination concurrently (claims 2-3) and, thereby reducing cancer cell proliferation, wherein the subject is medically compromised who is weakened or impaired medically (claim 1 and 37). Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is obvious because: 1) Deng’s teachings that cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) Lin taught combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44%; 3) PracticeUpdate taught astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 4) PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 5) Gengrinovitch taught intravenous administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration. One of ordinary skill in the arts would have been motivated, with a reasonable expectation of success, that treating AML via a method of administering Bcl-2 inhibitors would be an effective treatment for AML.
There is a reasonable expectation of success because Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent and explicitly taught the structure of the cytarabine prodrug and: 1) cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44% in humans; 3) astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 4) astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 5) intravenous administration is a known effective route of administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
Further, in regards to instant claims 1-3, as administrations of the two compositions may only be done concomitantly or sequentially, the limitations regarding the sequence of administrations are met.
In regards to instant claim 36, as the method of administering a compound represented by the structure of formula (1) and a Bcl-2 inhibitor concurrently to a relapsed or refractory AML patient wherein the subject is medically compromised who is weakened or impaired medically is taught by the prior art as discussed above, the limitation of “wherein the administering results in a reduction in side effects in the subject, wherein the side effects comprise at least one of mucositis, diarrhea, or alopecia, relative to side effects observed in subjects treated with cytarabine and the at least one additional anti-neoplastic agent or a second pharmaceutical composition comprising cytarabine and the at least one additional anti-neoplastic agent” would necessarily follow. Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-4, 6-7, 17, 21-26, 30, 32-33, and 36-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 8,993,278 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007), and Fasinu (Fasinu et al. Biopharmaceuticals & Drug Disposition (2011), Vol. 32, pages 185-209, reference of record).
The claims of the ‘278 patent in view of Gengrinovitch, PracticeUpdate, Deng, and Lin teach the limitations of claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 for the reasons set forth above.
‘278 does not teach the pharmaceutically acceptable salt of the compound of formula (1) is a salt of hydrochloric acid.
This deficiency is addressed by Fasinu.
The teachings of ‘278, Gengrinovitch, PracticeUpdate, Deng, Lin, and Fasinu are discussed supra.
Regarding claims 4 and 6, in the absence of unexpected results, the formulation of an amino acid-cytarabine conjugate of ‘278 into a pharmaceutically acceptable salt thereof using a known, conventional organic or inorganic acid useful for cytarabine (e.g, HCl or acetic acid) by known process; and the administration of pharmaceutically acceptable salt of an amino acid-cytarabine conjugate of ‘278 for the treatment method of AML of ‘278, Gengrinovitch, PracticeUpdate, Deng, and Lin above would have been prima facie obvious to one of ordinary skill in the art at the time of the instant filing. All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-3, 7, 17, 21-26, 30, and 32-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 8,993,278 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007), and Zuckerman T et al. (Blood (2015) 126 (23): 3810).
The claims of the ‘278 patent in view of Gengrinovitch, PracticeUpdate, Deng, and Lin teach the limitations of claims 1-3, 7, 17, 21-26, 30, 32-33, and 36-37 for the reasons set forth above.
‘278 does not teach administration of the compound of formula (1) to the subject at a dose of about 0.8 g/m2 to about 6 g/m2 of the subject's body surface area per day, but this is addressed by Zuckerman.
The teachings of ‘278, Gengrinovitch, PracticeUpdate, Deng, Lin, and Zuckerman are discussed supra.
Regarding instant claims 34-35, Zuckerman taught astarabine, a pro-drug of cytarabine – with an identical structure to instant formula (I) –, is safe and very well tolerated, including patients over 80 years of age, and resulted in complete remission in 3 of 9 patients with acute leukemia (page 2, conclusions). Regarding instant claims 34-35, Zuckerman taught relapsed/refractory AML patients were dosed with 0.5 g/m2 to 4.5 g/m2 astarabine and the dosage was effective (abstract).
Regarding claims 34-35, one of ordinary skill in the arts would have been motivated to, with a reasonable expectation of success, administer the structure of instant formula (1) in relapsed/refractory AML because it is safe and very well tolerated, in patients with relapsed/refractory AML including in patients over 80 years of age, wherein treatment with dosages of 0.5 g/m2 to 4.5 g/m2 resulted in complete remission in 3 of 9 patients with acute leukemia.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-4, 6-7, 17, 21-26, 30, and 32-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,058,701 B2 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015), Deng (Exp Ther Med. 2017 Aug;14(2):1081-1085., published online 6/16/2017, reference of record), and Lin TL et al. (Journal of Clinical Oncology 2016 34 15_suppl 7007).
Regarding instant claims 1, and 36-37, patented claim 1 taught a method of treating a cancer in a subject afflicted with the cancer comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the structure of formula (1):
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Regarding instant claim 37, patented claims 1 and 10 taught the pharmaceutical compound comprises a pharmaceutically acceptable excipient.
Regarding instant claims 4 and 6, patented claims 5 and 13 taught the pharmaceutical compound comprises a pharmaceutically acceptable salt wherein the salt is hydrochloric acid.
Regarding instant claims 34-35, patented claim 2 taught the compound is administered at a daily dose of at least 2.5 g/m², 3 g/m² of the subject's surface area.
Regarding instant claims 23-24, patented claims 7 and 9 taught a method of treating AML and MDS.
Regarding instant claims 32-33 and 37 wherein a liquid for intravenous administration would require a liquid excipient, patented claim 10 taught parenteral and intravenous administration.
The U.S. patent does not teach administering a second pharmaceutical composition comprising a therapeutically effective amount of at least one additional anti-neoplastic agent, wherein the first and second pharmaceutical compositions are administered to the subject concurrently or sequentially, thereby reducing cancer cell proliferation in the subject.
The U.S patent does not claim human subjects.
The U.S. patent does not explicitly teach the subject is an elderly human is 70 or more years of age.
The U.S. patent does not claim that the at least one anti-neoplastic agent is venetoclax.
The U.S. patent does not claim the anti-neoplastic agent is bound or attached to immune cells capable of inhibiting cancer cell growth, wherein the immune cells are chimeric antigen receptor T cells (CART)
The U.S. patent does not claim the CART is CART123.
These deficiencies are made up for by Gengrinovitch, PracticeUpdate, Deng, and Lin.
Gengrinovitch, PracticeUpdate, Deng, and Lin are described above.
Regarding instant claims 1-4, 6-7, 17, 21-26, 30, 32-35, and 37, it would have been obvious to a person having ordinary skill in the art to modify the method of patented claims 1-2, 5, 7, 9-10, 13, for treating a human with AML with the cytarabine containing prodrug compound of the structure
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and a pharmaceutically acceptable HCl salt form and a pharmaceutically acceptable excipient composition intravenously at a dose of 2.5 g/m2 of the subjects surface area – and to include: 1) concurrent combination CAR T Cell therapy with CART-123 cells as taught by Deng; 2) concurrent combination treatment with ABT-199 (venetoclax) as taught by Lin; 3) treatment of older patients with relapsed/refractory AML disease as taught by PracticeUpdate; and 4) treatment wherein the subject is medically compromised who is weakened or impaired medically as taught by PracticeUpdate.
This would produce a method of treating a human subject with relapsed or refractory (instant claim 30) AML (instant claims 25-26), which is a hematological leukemia (instant claims 23-24), by: a) administering a therapeutically effective amount of the anti-proliferative cytarabine prodrug with the structure:
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of the HCl salt (instant claims 4 and 6) with a pharmaceutically acceptable excipient, intravenously (claim 33)(which is a form of parenteral administration (claim 32), wherein the dosage is 2.5g/m2 of the subject’s surface area (instant claims 34-35) and b) administering a second pharmaceutical composition of the Bcl-2 inhibitor ABT-199 (venetoclax)(claim 7 and 17) and CART-123 cells (claim 22)(which have the anti-neoplastic CD123 targeting agent bound to the CART cell (claim 21)) in combination concurrently (claims 2-3) and, thereby reducing cancer cell proliferation, wherein the subject is medically compromised who is weakened or impaired medically (claim 1 and 37). Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is obvious because: 1) Deng’s teachings that cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) Lin taught combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44%; 3) PracticeUpdate taught astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; and 4) PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration. One of ordinary skill in the arts would have been motivated, with a reasonable expectation of success, that treating AML via a method of administering Bcl-2 inhibitors would be an effective treatment for AML.
There is a reasonable expectation of success because Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent and explicitly taught the structure of the cytarabine prodrug and: 1) cytarabine-induced AML cell apoptosis was enhanced by CTL treatment, and further, chimeric antigen receptor-modified T cell (CAR-T) treatment with CART-123 cells may improve the issues of specificity and cytotoxic competence; 2) combination treatment of venetoclax with cytarabine, which is the active drug of the instant prodrug, shows: a) synergy in several AML cell lines; and b) a higher overall response rate than cytarabine alone in AML patients ≥ 65 years not eligible for intensive chemotherapy, wherein the overall response rate of the combination treatment was 44% in humans; 3) astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; and 4) astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
Further, in regards to instant claims 1-3, as administrations of the two compositions may only be done concomitantly or sequentially, the limitations regarding the sequence of administrations are met.
In regards to instant claim 36, as the method of administering a compound represented by the structure of formula (1) and a Bcl-2 inhibitor concurrently to a relapsed or refractory AML patient wherein the subject is medically compromised who is weakened or impaired medically is taught by the prior art as discussed above, the limitation of “wherein the administering results in a reduction in side effects in the subject, wherein the side effects comprise at least one of mucositis, diarrhea, or alopecia, relative to side effects observed in subjects treated with cytarabine and the at least one additional anti-neoplastic agent or a second pharmaceutical composition comprising cytarabine and the at least one additional anti-neoplastic agent” would necessarily follow. Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-3, 7, 17, 21-26, 30, 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 17/920,183 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record) and PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015) and evidenced by Biosight (2023 https://www.biosight-pharma.com/aspacytarabine, reference of record).
Regarding instant claims instant claims 1-3, 17/920,183 taught a method of treating a hematological cancer comprising administering aspacytarabine (evidenced by Biosight as the same as instant formula I
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, page 1) or a pharmaceutically acceptable salt and at least one other anti-hematological (same as anti-neoplastic) agent in combination (pending claim 4) in a series of therapy courses (pending claims 1-3, 5-17, and 32) with aspacytarabine administered prior or sequentially to the additional therapeutic.
Regarding instant claims 23-26, 17/920,183 taught the hematological cancer as AML (pending claim 19) or other specific forms of hematological cancers (pending claims 19-20).
Regarding instant claims 7, 17, 21-22, 26, 32-35, and 36-37, 17/920,183 anticipates the additional agents for combination therapy as a BCL2 inhibitor or CART-123 (pending claims 21 and 30) and specifically venetoclax (pending claims 22-25), with an aspacytarabine dose of 0.3 to 10 g/m2/day and 1.5, 2.3, or 4.5 g/m2/day (pending claims 27-29), which improves survival (pending claim 31).
‘183 does not teach: 1) the cancer patient treated is a medically compromised human who is weakened or impaired medically; 2) the subject has relapsed or refractory AML; and 3) the aspacytarabine administered intravenously, but this is obvious in view of PracticeUpdate and Gengrinovitch.
‘183, Gengrinovitch and PracticeUpdate are described above.
Regarding instant claims 1-3, 7, 17, 21-26, 30, 32-35, and 37, it would have been obvious to a person having ordinary skill in the art to modify the method of copending claims 1-17, 19-25, 27-31 for treating a human with AML with the cytarabine containing prodrug compound of the structure
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and a pharmaceutically acceptable salt form in combination with either CART-123 or venetoclax with a dose of 1.5 to 4.5 g/m2 of the prodrug – and to include: 1) treatment of older patients with relapsed/refractory AML disease as taught by PracticeUpdate; 2) treatment wherein the subject is medically compromised who is weakened or impaired medically as taught by PracticeUpdate; and 3) intravenously administer the prodrug as taught by Gengrinovitch.
This would produce a method of treating a human subject with relapsed or refractory (instant claim 30) AML (instant claims 25-26), which is a hematological leukemia (instant claims 23-24), by: a) administering a therapeutically effective amount of the anti-proliferative cytarabine prodrug with the structure:
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of with a pharmaceutically acceptable excipient, intravenously (claim 33)(which is a form of parenteral administration (claim 32) with a dosage of 1.5 to 4.5 g/m2 of the prodrug (instant claims 34-35) and b) administering a second pharmaceutical composition of the Bcl-2 inhibitor ABT-199 (venetoclax)(claim 7 and 17) and CART-123 cells (claim 22)(which have the anti-neoplastic CD123 targeting agent bound to the CART cell (claim 21)) in combination concurrently (claims 2-3) and, thereby reducing cancer cell proliferation, wherein the subject is medically compromised who is weakened or impaired medically (claim 1 and 37). Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is obvious because: 1) PracticeUpdate taught astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 2) PracticeUpdate taught astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 3) Gengrinovitch taught intravenous administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
There is a reasonable expectation of success because Gengrinovitch taught the amino acid drug conjugate may serve as a delivery vehicle for a prodrug in which the drug undergoes rapid uptake by cancer cells to increase or improve bioavailability of the active agent compared to administration of the active agent without the delivery agent and explicitly taught the structure of the cytarabine prodrug and: 1) astarabine, a prodrug of cytarabine which has an identical structure of instant formula (1), is safe and well tolerated in patients over 80 years of age, and resulted in complete remission in a secondary AML patient with relapsed/refractory disease; 2) astarabine acts as a targeted therapy in leukemia which: a) spares other tissues and thus can be given to patients with comorbidities; and b) can be delivered in higher doses with an anticipated better antileukemic effect; and 3) intravenous administration is a known effective route of administration of the prodrug. Thus, patients that are impaired medically with comorbidities would not suffer from toxicity to non-cancerous tissues and could receive the combination treatment. Further, PracticeUpdate taught combination therapy using astarabine combined with other targeted therapies will prolong remission duration.
Further, in regards to instant claims 1-3, as administrations of the two compositions may only be done concomitantly or sequentially, the limitations regarding the sequence of administrations are met.
In regards to instant claim 36, as the method of administering a compound represented by the structure of formula (1) and a Bcl-2 inhibitor concurrently to a relapsed or refractory AML patient wherein the subject is medically compromised who is weakened or impaired medically is taught by the prior art as discussed above, the limitation of “wherein the administering results in a reduction in side effects in the subject, wherein the side effects comprise at least one of mucositis, diarrhea, or alopecia, relative to side effects observed in subjects treated with cytarabine and the at least one additional anti-neoplastic agent or a second pharmaceutical composition comprising cytarabine and the at least one additional anti-neoplastic agent” would necessarily follow. Further, the said cancer cell proliferation would naturally be reduced by a synergistic inhibitory effect of the combination treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Claims 1-4, 6-7, 17, 21-26, 30, 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 17/920,183 in view of Gengrinovitch (US 20110275590 A1, published 11/10/2011, reference of record), PracticeUpdate (https://www.practiceupdate.com/content/astarabine-a-pro-drug-of-cytarabine-appears-safe-in-patients-with-advanced-acute-leukemia/32765, published 12/8/2015) and Fasinu (Fasinu et al. Biopharmaceuticals & Drug Disposition (2011), Vol. 32, pages 185-209, reference of record).
The claims of the ‘183 patent in view of Gengrinovitch and PracticeUpdate, teach the limitations of claims 1-3, 7, 17, 21-26, 30, 32-37 for the reasons set forth above.
‘183 does not teach the pharmaceutically acceptable salt of the compound of formula (1) is a salt of hydrochloric acid.
This deficiency is addressed by Fasinu.
The teachings of ‘183, Gengrinovitch, and PracticeUpdate and Fasinu are discussed supra.
Regarding claims 4 and 6, in the absence of unexpected results, the formulation of an amino acid-cytarabine conjugate of ‘183 into a pharmaceutically acceptable salt thereof using a known, conventional organic or inorganic acid useful for cytarabine (e.g, HCl or acetic acid) by known process; and the administration of pharmaceutically acceptable salt of an amino acid-cytarabine conjugate of ‘183 for the treatment method of AML of ‘183, Gengrinovitch, and PracticeUpdate above would have been prima facie obvious to one of ordinary skill in the art at the time of the instant filing. All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant has amended the independent claims 1 and 36-37 to include wherein said subject is a medically compromised human who are weakened or impaired medically. The elected species of: (iv) MDS and (v) an elderly human, are no longer claimed in the instant claim set. The next species searched are (iv) acute myeloid leukemia (AML); and (v) relapsed or refractory hematological cancer.
The updated rejections are above.
Applicant argues unexpected results.
In response, Applicant's arguments dated 8/12/2024 have been considered but are not found persuasive. Applicant’s arguments regarding unexpected results and the response are described above.
Conclusion
No claims are allowed.
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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643