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
1. Claims 1-14 are pending in the current application.
2. This application is a 371 of PCT/US2022/025960 04/22/2022.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 63/274,489 and 63/178,800, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The ‘800 application has only the 2-chloro-6-aminopurine compound. The ‘489 has both 2-chloro-6-aminopurine and 6-(Dimethylamino)purine administered separately. Neither application has a treatment with a “combination”. Neither application has the limitations of claims 5-6, 11, 13 or 14. Claims 1, 4-7, 10-14 are afforded the date of the filing of the international application 04/22/2022. Claims 2 and 8 are afforded the filing date of the ‘800 application 04/23/2021. Claims 3 and 9 are afforded the filing date of the ‘489 application 11/01/2021.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 1-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 1 and 7 are drawn to treatment with “a therapeutically effective amount of an adenine analog selected from the group consisting of:…..C. and combinations thereof.” Combinations is not “an adenine analog”. MPEP § 2173.05(h), states “A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196.” Combinations is not a member. Claim 6 has a similar issue with the list “selected from the group consisting of furosemide, vaptans and combinations thereof”.
5. Claims 1-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims are drawn to “racemate, optical isomer”. None of the claimed compounds are chiral, and as such the terms racemate, and optical isomer have no definite meaning when applied to an achiral compound.
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.
6. Claim(s) 7-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Helal “Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease” Nephrol Dial Transplant 2013, 28, 380–385, Sircar “Efficacy of Febuxostat for Slowing the GFR Decline in Patients With CKD and Asymptomatic Hyperuricemia: A 6-Month, Double-Blind, Randomized, Placebo-Controlled Trial.” Am J Kidney Dis. 2015, 66(6):945-950 AND Krenitsky “A Comparison of the Specificities of Xanthine Oxidase and Aldehyde Oxidase” ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 1972, 150, 585-599. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Helal explains that “Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD).” [page 380] “Because hyperuricemia may be a modifiable risk factor for the progression to ESRD in ADPKD, we undertook this retrospective study in a large cohort of ADPKD patients to explore whether hyperuricemia, independent from renal function, is associated with faster progression, as manifest by early-onset hypertension, larger kidney volumes and ESRD at a younger age.” The conclusions on page 384 explain how xanthine oxidase inhibitors would treat ADPKD, the main form of polycystic kidney disease:
In summary, in this observational study, we show that elevated uric acid levels are associated with an early onset of hypertension in men and women with ADPKD and with younger age at the onset of ESRD, independent from age and renal function at study visit, and independent from BMI and use of medications such as ACEI, ARB, diuretics and allopurinol. Part of the association with earlier onset of ESRD is mediated by early onset of hypertension. Elevated uric acid levels may be a marker of decreased renal blood flow in ADPKD, but may also directly contribute to progression by inducing endothelial dysfunction and oxidative stress. An interventional trial with a xanthine oxidase inhibitor is needed to determine whether treatment of hyperuricemia confers clinical benefits in ADPKD.
Sircar on page 945 discusses the high levels of uric acid in kidney disease in a similar manner to Helal, “Hyperuricemia has been associated with adverse outcomes in CKD. Hyperuricemia has been linked to macrovascular heart disease in diabetic CKD.1 High uric acid levels have been reported to be associated with increased rates of decline in glomerular filtration rate (GFR) in cross-sectional studies.2,3 Febuxostat is a xanthine oxidase inhibitor shown to be efficacious in hyperuricemia and gout.4 It does not require dose modification in patients with kidney failure. Therapy with febuxostat has been shown to prevent renal damage in 5/6 nephrectomized rats….In this context, we hypothesized that febuxostat might retard the progression of kidney disease in patients with CKD and hyperuricemia.” Sircar ran a clinical trial and found the Xanthine Oxidase Inhibitor therapy with febuxostat was effective, “In conclusion, this single-center, double-blind, randomized, parallel-group, placebo-controlled study showed that febuxostat slowed the decline in eGFR in individuals with CKD stages 3 and 4 and asymptomatic hyperuricemia compared to placebo.”
Krenitsky on page 591in Table II shows that both compound a., 2-chloro-6-aminopurine, and compound b., 6-Dimethylamino purine are potent xanthine oxidase inhibitors:
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Ascertaining the differences between the prior art and the claims at issue.
The claims differ from the prior art in the identity of the xanthine oxidase inhibitor used to treat the kidney disease. Helal suggests that generally any xanthine oxidase inhibitor may be used, while Sircar uses febrostat. The lacuna is filled by Krenitsky who teaches the claimed compounds which have the property necessary to treat polycystic kidney diseases.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
Since elevated uric acid levels are associated with ADPKD and correlated with declines renal function. The Helal study of 680 patients showed that higher uric acid was associated with earlier onset of hypertension, larger kidney volume, and increased risk of ESRD. There are many biochemical mechanisms by which hyperuricemia can worsen cyst growth or kidney function in PKD as discussed in Sircar and Helal. Xanthine oxidase is an enzyme involved in purine metabolism, breaking down hypoxanthine to xanthine and xanthine to uric acid. Inhibiting xanthine oxidase would naturally reduce uric acid levels. This was already a known therapy and the patients who received xanthine oxidase inhibitor, febuxostat, treatment, the annual eGFR decline was decreased as discussed in Sircar. Simply substituting one known xanthine oxidase inhibitor for another as disclosed by Krenitsky is prima facie obvious. Regarding the combination, c., combining two things known for the same purpose in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine a. and b. for the same treatment. Regarding claim 11 at least Febuxostat, which treated CKD would be combined, other such agents are also known. Regarding the dosages in claim 10, the optimal dosage can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art. The routes of administration in claims 12-14 are standard and conventional.
7. Claim(s) 1-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Helal, Sircar AND Krenitsky as applied to claims 7-10, 12-14 above, and further in view of Guay-Woodford “Consensus Expert Recommendations for the Diagnosis and Management of Autosomal Recessive Polycystic Kidney Disease: Report of an International Conference” THE JOURNAL OF PEDIATRICS 2014, Vol. 165, No. 3 611-617. Claim 1 is drawn to a patient having hyponatremia as symptom. According to Guay-Woodford page 165 col 1, “Hyponatremia. Hyponatremia is common in ARPKD, with a reported incidence of 6%-26%.1,27”. As such a subpopulation of patients treated for ARPKD with the claimed compounds would have hyponatremia. Treating any of the ARPKD patients is obvious as discussed above, and the physician would not discriminate between the hyponatremic and non-hyponatremic patient.
8. Claim(s) 1-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Robins, Roland K. “Antitumor Activity and Structural Relationships of Purine Derivatives and Related Compounds against Neoplasms in Experimental Animals” Journal of Medicinal Chemistry (1964), 7(2), 186-99, Nakashima “Apoptosis induced by an alkylated purine, 6-dimethylaminopurine, and changes in gene expression in human lymphoma U937 cells.” Anticancer Research, 28(2A), 609-620 2008 AND CASTILLO, “Diagnosis and Management of Hyponatremia in Cancer Patients” The Oncologist 2012;17:756–765. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Robins showed that compound a. 2-amino-6-chloropurine was an anticancer agent in Table I on page 188:
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The second compound in claim 1, compound b, 6-dimethylaminopurine (6-DMAP) was the first compound to be identified as a CDC2 (CDK1, CDC28A, P34CDC2, cyclin-dependent kinase 1, cyclin dependent kinase) inhibitor. Nakashima shows that 6-DMAP initiates apoptosis (cell killing) by protein kinase inhibition through several mechanisms. “It has been found that the activation of cyclin A dependent protein kinases is an important event in apoptosis induction by 6-DMAP, indicating protein kinase inhibition.” [Nakashima page 610]. “It is recognized that 6-DMAP is an alkylated base and it has been reported that significant apoptosis of HeLa cells can be induced by 6-DMAP…. It is also reported that in Chinese hamster fibroblast cells, three alkylated purines (O6-methylguanine, 6-DMAP, O6- ethylguanine) induce apoptosis and that the p70 S6 kinase and MAP kinase pathways are involved (1). This study aimed to examine the further molecular mechanisms of p53- independent apoptosis induced by 6-DMAP in U937 cells. As shown in Figure 2, data on the rate of DNA fragmentation indicated that apoptosis was induced in a time and dose-dependent manner, which is morphologically apparent as shown in Figure 1.” [page 618].
According to Castillo on page 756 cancer patients are hyponatremic and often given tolvaptan, the limitation of claim 6 (vaptans),
Hyponatremia is an electrolyte abnormality commonly encountered in oncology practice and is usually defined by a serum sodium level 135 mEq/L [1, 2]. Although many cases are asymptomatic, hyponatremia may cause neurological symptoms, particularly when serum sodium declines rapidly or by a substantial extent [3]. The incidence and prevalence of hyponatremia vary greatly, depending on the cancer type, clinical setting, and serum sodium cutoff point [756]….Most cases of hyponatremia are caused by the syndrome of inappropriate antidiuretic hormone(SIADH),with higher rates of SIADH found with SCLC than with other malignancies [2,10]. However, hyponatremia—whether precipitated by SIADH, cancer treatment, or other underlying causes—may occur with other solid tumor types besides SCLC, as well as with hematological malignancies. This article identifies the rationale for diagnosis and management of hyponatremia in cancer patients, reviews its main causes, and then discusses treatment options, with a focus on the practical use of the arginine vasopressin(AVP)antagonist tolvaptan. [page 758]
Ascertaining the differences between the prior art and the claims at issue.
The instant claims are drawn to treating a symptom observed in cancer patients, hyponatremia, with two known anticancer drugs, either independently or in combination.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
Claim 1 is drawn to a patient having hyponatremia as a symptom. According to Castillo cancer patients are hyponatremic. The compounds in claim 1 are known anticancer agents. As such a subpopulation of patients treated for cancer with the claimed compounds would have hyponatremia. Treating the patients is obvious since the compounds were known anticancer agents. Regarding the combination, c., combining two things known for the same purpose, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine a. and b. for the same treatment. Regarding the dosages in claim 4, the optimal dosage can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
9. Claim(s) 7-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bukanov “Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine.” Nature. 2006;444:949–52, Roland and VESELY “Inhibition of cyclin-dependent kinases by purine analogues” Eur. J. Biochem. 224, 771-786 (1994). The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Bukanov explains, “Polycystic kidney diseases (PKDs) are primarily characterized by the growth of fluid-filled cysts in renal tubules leading to end-stage renal disease1–3.” [page 949]. “To determine the potential of CDK inhibition as a new therapeutic approach for the treatment of PKD we employed (R)-roscovitine (CYC202), a potent inhibitor of Cdk2–cyclin E with a 50% inhibitory concentration (IC50) of 0.1 mM as well as Cdk7–cyclin H (IC50 0.4 mM), Cdk9–cyclin T1 (IC50 0.8 mM) and Cdk5–p35–p25 (IC50 0.16 mM)13,14. It is currently in clinical trials as an anticancer agent15,16. We tested the effect of roscovitine on slowly progressive renal cystic disease in jck mice. The development of PKD in the jck mice resembles human disease in many ways, as described previously17. Thus, similarly to ADPKD, jck mice develop cysts in multiple nephron segments and display gender dimorphism with more aggressive disease in males. jck/jck males were injected daily with 50 and 150 mg kg21 roscovitine from day 26 to day 64 for a total of 5 weeks (Fig. 1a, b)…. The roscovitine-treated group showed a significant decrease in the ratio of kidney weight to body weight and in cystic volumes, in a dose-dependent manner (Fig. 1a, b, and Supplementary Table 1). In addition, blood urea nitrogen (BUN) was significantly decreased in the 50 mg kg21 roscovitine-treated group and normalized with 150 mg kg21 roscovitine (Fig. 1a). Roscovitine also effectively inhibited PKD in jck/jck females, in which the disease is less severe than in males (Supplementary Table 1).” In conclusion, “Our study shows for the first time the therapeutic potential for cell-cycle inhibition for the treatment of polycystic kidney diseases. Roscovitine is a selective inhibitor for CDKs with minimal off-target kinase activities19, making it a clinical candidate for ADPKD. We show that roscovitine effectively inhibited cystogenesis and improved renal function in jck and cpk models of PKD, with a long-lasting effect. Analysis of the molecular targets of roscovitine in cystogenesis showed that it acts through blockade of the cell cycle, transcriptional regulation and inhibition of apoptosis.” [Page 952]
Robins showed that compound a. 2-amino-6-chloropurine was an antiproliferative agent in Table I on page 188 as discussed above.
VESELY “Inhibition of cyclin-dependent kinases by purine analogues” Eur. J. Biochem. 224, 771-786 (1994) explains “Cyclin-dependent kinases (cdk) have recently raised considerable interest in view of their essential role in the regulation of the cell division cycle (cdc) [6, 71. cdk consist of a catalytic subunit, the prototype of which is cdc2, and a regulatory subunit (cyclin)….cdk1 (also known as cdc2) [page 771]… An increasing number of studies are providing data that support the importance of cdk protein deregulation in human tumor development [page 772] The frequent deregulation of cdk proteins in cancer and the recent discovery of natural inhibitors have stimulated an active search for chemical inhibitors of cdk proteins. Such cdk inhibitors could potentially act by various mechanisms, i.e. by interfering with the binding of substrates (ATP or protein), by affecting the binding of regulatory subunits (cyclins or by interacting with some sites involved in activation (Thrl61 in cdc2), by interacting with the nuclead cytoplasmic localization signals or by mimicking the natural inhibitor/cdk interactions.. [T]he N6 substituted adenine 6-dimethylaminopurine (2), first described as an inhibitor of cell division in embryos [31] and later identified as a p34cdc2/cyclin B kinase inhibitor”
Vessly describes the same cdk inhibition for compound b. as Nakashima, and also show that this is a general property of “C2, N6, and N9-substituted purines” which “were found to exert strong inhibitory effects on the cdc2, cdk2, cdk5 and ERK1 kinases, but not on cdk4 and cdk6 (among 35 kinases tested). Analysis of structure/activity relationships for more than 80 purine derivatives allows speculation on the molecular interactions between these inhibitors and cdk proteins.” Table 2 details a wide variety of purines that inhabit cdc2 (cdk1) in the first column and entry 2 discloses 2,6-dimethylaminopurine. Other compounds including the chloro amino purine (entry 46).
Ascertaining the differences between the prior art and the claims at issue.
Bukanov used one antiproliferative cyclin-dependent kinases (Cdk) inhbitor roscovitine to treat PKD. The instant claims are drawn to substituting two other known cdc2 (cdk1) inhibitor antiproliferative agents, either independently or in combination to treat polycystic kidney disease.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck)mice. Using additional antiproliferative agents known to inhibit Cdks in the same or similar manner would be expected to treat the polycystic kidney disease in the same way. Simply substituting one inhibitor for another is prima facie obvious.
Claims 11 is drawn to combining the compounds of claim 7, with additional drugs that treat the same condition. This property of “inhibiting cyst fluid filling and cyst growth” was already shown in the mice of Bukanov treated with roscovitine (“significant decrease in….cystic volumes, in a dose-dependent manner (Fig. 1a, b, and SupplementaryTable 1)”).. Combining two things known for the same purpose, treating PKD, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine roscovitine with compounds a. and/or b. for the same treatment. According to Bukanov page 952 col. 1 “Multiple treatment options are needed to target PKD, and it is likely that combination therapies may prove most effective.” Regarding the dosages in claim 10, the optimal dosage can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art. The routes of administration in claims 12-14 are standard and conventional.
Information Disclosure Statements
10. The information disclosure statements fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because NPL document 21 is cited without a date. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Conclusion
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621