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 .
Claim Status
Claims 1-13 were previously pending.
By virtue of the 06 August 2024 Preliminary Amendment, claims 1-13 were amended by applicant. No claim was added or cancelled.
Therefore, claims 1-13 remain pending and currently under examination.
Priority
Examiner acknowledges applicant’s claim to the following priority:
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Information Disclosure Statement (IDS)
The IDSs (2) filed on 06 August 2024 and 20 February 2026 have been considered by the examiner. Signed copies are enclosed.
Claim Objections
Claim 1 contains what appears to be a typographical error: “[a] method for treating a cardiovascular disease comprising: administering…to a subject having a serum uric acid concentration of 6 mg/dl or more, administering decreases the serum uric acid concentration of the subject…”
Grammatically speaking, the claim should state, “wherein the administering decreases” as it appears applicant intended:
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Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administration of allopurinol and febuxostat for reducing serum uric acid in certain subjects, does not reasonably provide enablement for the full scope of the claimed methods of treating and/or preventing cardiovascular disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)).
These include: the breadth of the claims, the nature of the invention, the state of the
prior art, the level of one of ordinary skill, the level of predictability in the art, the amount
of direction provided by the inventor, the existence of working examples, and the
quantity of experimentation needed to make or use the invention.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The breadth of the claims:
This factor weighs strongly against enablement.
Independent claim 1 is not limited to merely lowering serum uric acid to below 6 mg/dl. Rather, claim 1 requires “treating a cardiovascular disease” by administering allopurinol or febuxostat to any subject having a cardiovascular disease and a serum uric acid concentration of 6 mg/dl or more.
The breadth of ‘cardiovascular disease’ is particularly significant because the specification defines the term to include: coronary heart disease, coronary vascular disease, arteriosclerosis, hypertension, angina pectoris, myocardial infarction, acute renal failure, congestive cardiac failure, peripheral vascular disease, heart attack, arrhythmia, tachycardia, stroke, transient ischemic attack, and cerebrovascular disease ([0043]).
The specification also defines ‘treatment’ broadly to include: reversal, alleviation, inhibition of progression, or prevention of the disease or one or more symptoms, and states that the claimed compositions may be used for chronic treatment as well as treatment over a specified period ([0045]).
Claim 1 does not require the subject has gout, a prior major cardiovascular event, any specific cardiovascular diagnosis, any particular age, or any particular cardiovascular risk factor. Nor does claim 1 require any specific duration of therapy, any degree of cardiovascular benefit, any particular dose, any particular degree of renal function, or selection of one of the allegedly responsive subgroups identified in the specification.
Claim 1 therefore encompasses substantially more than reducing the probability of a composite cardiovascular endpoint in a particular cohort. Treatment includes both therapeutic and prophylactic effects. This breadth is substantially greater than the population actually investigated by the applicant.
Claim 2 further expands the breadth to include prevention of a major cardiovascular event in the subject. These major cardiovascular events include death from cardiovascular disease, a myocardial infarction, a stroke, or angina ([0054]).
Claims 10-13 add specific doses or titration procedures, but do not narrow the cardiovascular disease genus, and thus, continue to encompass the use of those dosing regimens to treat or prevent every cardiovascular condition embraced by claim 1.
Nature of the invention:
This factor weighs against enablement.
The claimed invention concerns a therapeutic effect in human cardiovascular disease, not merely administration of a known compound or attainment of a known biochemical endpoint. Lowering serum uric acid is readily measurable. However, the claims require that the administration results in treatment or prevention of cardiovascular disease, and claim 2 additionally requires prevention of a broadly claimed major cardiovascular event.
The specification itself recognizes the distinction between lowering serum uric acid and treatment of cardiovascular disease. Paragraph [0035] explains allopurinol and febuxostat were known drugs for “hyperuricacidemia” (aka hyperuricemia) patients because inhibition of xanthine oxidase lowers uric acid. In contrast, paragraph [0037] states that their therapeutic effectiveness for cardiovascular disease has not been clearly revealed, multiple studies reporting the drugs make cardiovascular disease worse, and treatment of cardiovascular disease using allopurinol and febuxostat is not clinically attempted at all.
Paragraph [0002] is even more direct. Paragraph [0002] states that, although attempts have been made to prevent or treat cardiovascular disease using xanthine oxidase inhibitors, treatment efficacy for cardiovascular disease had not been clearly revealed, febuxostat increases risk of cardiovascular disease, oxidase inhibitors may cause side effects related to cardiovascular disease, and cardiovascular disease treatment using the inhibitors is not recommended or approved.
Thus, Applicant’s own disclosure distinguishes between the predictable urate-lowering pharmacology and the unpredictable therapeutic effect that comprises the claimed invention. This distinction weighs strongly toward necessitating meaningful guidance sufficient to enable cardiovascular treatment and prevention across the claimed scope.
State of the prior art:
This factor also weights against full scope enablement.
The specification acknowledges that allopurinol and febuxostat were known for treatment of hyperuricemia and gout and were further known to lower serum uric acid through xanthine oxidase inhibition. However, the specification also expressly states the cardiovascular treatment effect was not established in the art and that prior reports raised concerns that xanthine oxidase – particularly febuxostat – could adversely affect cardiovascular risk.
The causal relationship between lowering serum uric acid and lower cardiovascular risk is widely disputed in the art. Lee1, Brucato2, and Culleton3 demonstrate this:
Lee teaches the contradictory results regarding the therapeutic effects of urate-lowering treatment on the prevention and treatment of CVD (p. 1). Results from one study reported that the risk of cardiovascular events is lower in patients who are currently exposed to allopurinol than that in patients who were exposed to allopurinol in the past (p. 1). Lee further teaches febuxostat has shown beneficial effect in reducing cardiovascular events in patients with pre-existing CVD or heart failure and chronic kidney disease compared with that in patients who received allopurinol (p. 1). Yet, another larger study demonstrated the risk of cardiovascular or all-cause mortality was higher in febuxostat-treated patients than in allopurinol-treated patients (p. 1). In addition, Lee’s independent findings suggest that abrupt change in serum urate levels after allopurinol or febuxostat exposure was associated with an increased risk of cardiovascular events in patients with CVD and reduction of urate to the lowest levels was significantly association with the development of cardiovascular events (p. 3).
Brucato further teaches the lack of evidence correlating hyperuricemia and heart disease. One study in Denmark confirmed the relationship with CVD and hyperuricemia, but showed no evidence for the causal association between hyperuricemia, ischemic hear disease, and blood pressure (p. 9). The authors of that study did find a causal effect of body mass index (BMI) on uric acid, suggesting that BMI is a strong confounder in observational associations and highlighting the role of obesity in the development of related conditions (p. 9). Worth noting, however, is that established drugs frequently prescribed to reduce cardiovascular risk, such as beta-blockers, ACE-inhibitors, sartans other than losartan, and low-dose aspirin, actually raise serum urate levels, thus dispelling any correlation between raised uric acid levels and cardiovascular risk (p. 9). Regarding xanthine oxidase inhibitors (XOIs), in 2017 the FDA released a warning on a possible link between febuxostat and CVD (p. 14). Brucato then systemically reviewed all randomized controlled trials in which patients with asymptomatic hyperuricemia were exposed to XOIs allopurinol and febuxostat (p. 9) and found:
Allopurinol is often prescribed for AH to lower serum urate levels, although this use is not supported by conclusive evidence from prospective RCTs, nor is it recommended by guidelines (p. 16);
XOIs are not recommended for cardiovascular prophylaxis in patients with AH; and
More long-term data on benefits on hard end-points in CVD such as deaths, myocardial infarction, stroke, and CKD, and data on safety and pharmacological interactions are needed, particularly in specific subgroups of patients such as the elderly, very elderly, patients in secondary prevention for CVD and those with different degrees of chronic renal failure (p. 16).
Finally, Culleton teaches uric acid does not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes and any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors (p. 7).
Therefore, the state of the art does not cure the lack of disclosure across the therapeutic scope claimed.
Level of ordinary skill in the art:
This factor weight somewhat in favor of Applicant, but does not overcome the deficiencies.
A person of ordinary skill would have understood: allopurinol and febuxostat pharmacology; serum uric acid measurement; conventional doses; renal function-based dose adjustment; diagnosis of gout and hyperuricemia; cardiovascular endpoints; and conventional clinical study methodology.
Accordingly, substantial experimentation would not have been required merely to administer the drugs or lower serum uric acid. However, the claimed invention is not directed to administration only and requires treatment/prevention of cardiovascular disease. Even a highly skilled clinician or researcher would not, from routine skill alone, be able to predict that attainment of serum urate less than 6 mg/dl with either XOI would reverse, alleviate, prevent, or inhibit progression of every cardiovascular disorder encompassed by the claims, particularly when the disclosure itself states that cardiovascular efficacy is so uncertain. Therefore, the high level of skill reduces experimentation concerning drug administration but does not supply the missing therapeutic correlation across the claimed cardiovascular disease genus.
Predictability of the art:
This factor weighs strongly against enablement. Cardiovascular therapeutic outcomes in heterogeneous human populations are inherently less predictable than the biochemical effect of lowering serum urate. The specification itself demonstrates this unpredictability.
Applicant does not state that every cardiovascular subject who attains serum urate less than 6 mg/dl obtains cardiovascular benefit. Instead, paragraph [0042] states that “it may be an important task to confirm a cardiovascular disease subject group who responds with an effective prevention or treatment effect by administering a xanthine oxidase inhibitor such as allopurinol and febuxostat.” Yet, does not disclose how to screen for such patients. This disclosure is inconsistent with an expectation that cardiovascular therapeutic benefit predictably follows from administration of allopurinol or febuxostat, a uric acid reduction of less than 6 mg/dl, in the subject population covered by claim 1.
The prior art does not cure this unpredictability. Instead, as discussed above, there is no consensus within the prior art. Some studies show the relationship between CVD and hyperuricemia, while others, including an FDA warning, show that XOI drugs which lower uric acid may actually cause CVD. Accordingly, the art is not sufficiently predictable to justify extrapolating the disclosure to the full scope of claim 1.
Amount of direction or guidance provided in the specification:
This factor weighs against enablement of the full scope.
The specification provides substantial guidance regarding how to lower serum urate. For example, it describes allopurinol doses from 100-600 mg/day; allopurinol titration according to renal function; febuxostat doses from 20-120 mg/day; febuxostat titration from 40 mg to 80 mg when urate remains greater than or equal to 6 mg/dl; and monitoring of serum uric acid ([0063]-[0072]).
While applicant’s specification is sufficient to enable lowering uric acid, there is a huge leap between determining that lowering uric acid with one of the claimed agents will treat/prevent the particular cardiovascular disease of the particular subject across the full scope claimed. Nor does the specification instruct one skilled in the art how to select: allopurinol versus febuxostat for a particular cardiovascular disease; subjects outside the identified responsive subgroups; subjects without gout; subjects having cardiovascular diseases not represented by the trial population; appropriate cardiovascular endpoints for each claimed disease; or circumstances in which reduction of uric acid will or will not confer the claimed cardiovascular treatment effect. Instead, paragraph [0042] expressly teaches that subject groups having “excellent effect when treated with…allopurinol and febuxostat” should be selected. Yet, claim 1 does not require selection of such group and the specification does not provide guidance on selection of such group. Accordingly, the specification identifies the problem of treatment response heterogeneity, but does not provide a general teaching by which one skilled in the art could identify operable embodiments throughout the claimed scope without significant additional clinical investigation.
Working examples:
This factor weighs partially in Applicant’s favor, but the examples are not commensurate with the claimed scope.
The specification includes a human clinical dataset derived from a multicenter, randomized, double-blind cardiovascular trial involving subjects with gout and a history of major cardiovascular disease. Paragraph [0079] states that participants were diagnosed with gout satisfying ACR criteria and a history of major cardiovascular disease, including myocardial infarction, unstable angina requiring hospitalization, stroke, TIA, peripheral vascular disease, or diabetes-related cardiovascular risk.
The trial compared febuxostat and allopurinol and used a primary composite cardiovascular endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina ([0092]). The specification reports 6,198 subjects in the analyzed population and describes the administered doses ([0096]). However, the clinical trial was expressly designed to evaluate non-inferiority of febuxostat to allopurinol with respect to cardiovascular risk, rather than prospectively to establish that lowering uric acid below 6 mg/dl with either drug treats the broad universe of cardiovascular diseases claimed.
Applicant thereafter performed subgroup analyses based on whether subjects maintained serum uric acid below 6 mg/dl versus at or above 6 mg/dl and based on various subject characteristics such as age and BMI.
Thus, the working evidence is fundamentally narrower than the claims in several respects:
The population had gout;
The population had pre-existing major cardiovascular disease/risk;
The endpoint was a composite MACE endpoint;
The asserted therapeutic conclusion arose from subgroup analysis according to attained serum uric acid and biomarkers; and
Different subgroups of subjects behaved differently.
Even the claimed biomarker of serum uric acid concentration of less than 6 mg/dl does not, in itself, indicate the therapeutic treatment was effective as treatment was continued even after passing this threshold ([0099]).
A working example need not encompass every claimed embodiment. However, in an unpredictable field, the question is whether one skilled in the art would reasonably understand from the disclosed examples and general teaching how to practice the full scope without undue experimentation. The presently disclosed clinical dataset does not supply such a generalizable teaching.
Quantity of experimentation required:
This factor weighs strongly against enablement.
To practice the full scope of claim 1, one skilled in the art would need to determine whether lowering serum uric acid below 6 mg/dl with allopurinol or febuxostat actually provides the claimed cardiovascular therapeutic and preventative effect across numerous materially different cardiovascular diseases and patient populations not disclosed by Applicant.
This investigation would require more than routine dose adjustment or serum urate monitoring. For untested portions of the claim, the skilled artisan would need to determine, for example:
Whether either drug treats hypertension by virtue of lowering urate;
Whether either drug treat arrythmias;
Whether either drug treats congestive heart failure;
Whether either drug treats arteriosclerotic disease;
Whether the treatment works in subjects who do not have gout;
Whether benefits observed in prior MACE gout patients extrapolate to other cardiovascular populations;
Whether both allopurinol and febuxostat provide comparable cardiovascular therapeutic benefit;
Which subject characteristics predict benefit or lack of benefit;
The duration of treatment required; and
The appropriate cardiovascular clinical endpoint for each condition.
These questions could not be answered merely by performing a routine laboratory assay. They would require additional controlled human cardiovascular studies or substantial clinical investigation in distinct disease and patient populations.
The specification’s own methodology illustrates the scope of that undertaking. The disclosed study involved thousands of patients, hundreds of study sites, extended follow-up appointments, adjudication of cardiovascular endpoints, and subgroup statistical analyses. This is not permissible through routine optimization. Rather, it amounts to requiring one skilled in the art to discover, through further substantial clinical experimentation, which portions of the claimed genus work for the claimed therapeutic/preventive purpose.
Other than contemplating a method of lowering serum uric acid by administering allopurinol, febuxostat, or a salt thereof, the specification does not disclose how to treat or prevent cardiovascular disease in a subject with a uric acid concentration of 6 mg/dl or more. As clearly stated in Genentech Inc. v. Novo Nordisk NS (CAFC) 42 USPQ2d 1001: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” See also Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), stating in the context of the utility requirement that “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.”
Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention, to which the instantly filed disclosure is largely silent, as set forth above. In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to use the claimed invention. Therefore, claims 1-13 are not considered to be enabled by the instant disclosure regarding the treatment and prevention of claimed diseases.
The rejection under 35 USC 112(a) is based on the failure of the specification to enable the full scope of the claimed cardiovascular treatment methods without undue experimentation. The separate rejection under 35 USC 103 below is based on the teachings of the prior art, which disclose or suggest particular embodiments falling within the scope of the claims. These grounds are not inconsistent because the prior art may render particular claimed embodiments obvious while the specification nevertheless fails to provide an enabling disclosure commensurate with the full breadth of the claims. This type of treatment is limited to those art areas in which the teachings and suggestions in the art are in conflict with one another (see Patent Examination Policy - MPEP Staff - 35 USC 112 1st para - Enablement of Chemical/Biotechnical Applications (III)(C)(3)).
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 1-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over White (cited by applicant in 06 August 2024 IDS as: “Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout,” published: 12 March 2018), and in further view of Larsen (“Effect of Allopurinol on Cardiovascular Outcomes in Hyperuricemic Patients: A Cohort Study,” published: 14 November 2015) and Rodriguez-Martin (“Risk of Acute Myocardial Infarction Among New Users of Allopurinol According to Serum Urate Level: A Nested Case-Control Study,” published: 05 December 2019).
Regarding claim 1 –
White teaches a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease with either allopurinol or febuxostat (p. 1200). White randomized 6,190 such cardiovascular disease patients to allopurinol or febuxostat treatment and evaluated cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent vascularization (p. 1200).
White teaches study inclusion criteria as serum urate of at least 7.0 mg/dl or of at least 6.0 mg/dl with inadequately controlled gout (p. 1201). White teaches patients who had an estimated creatine clearance of at least 30 but less than 60 ml per minute initially received 200 mg of allopurinol and the dose was increased in 100-mg increments until the patient either had a serum urate level of less than 6.0 mg/dl or was receiving an allopurinol dose of 400 mg once daily (pp. 1201-02). White further teaches maintenance of serum urate levels of less than 6.0 mg/dl during treatment with febuxostat or allopurinol. (p. 1203).
White therefore teaches all the treatment steps of claim 1, including administering allopurinol or febuxostat to a subject with cardiovascular disease and elevated serum urate above 6 mg/dl and titrating the drug to reduce serum urate below 6 mg/dl.
To the extent White does not expressly characterize such administration as treating the cardiovascular disease, Larsen teaches that treatment of hyperuricemic patients with allopurinol was associated with a statistically significant reduction in cardiovascular risk (abstract). Larsen specifically studied patients with serum urate >6 mg/dl and reported decreased occurrence of a composite endpoint comprising myocardial infarction, stroke, and cardiovascular death among allopurinol treated patients.
Moreover, Rodriguez-Martin teaches that long-term administration with allopurinol was associated with reduced acute myocardial infarction risk and that this particular cardiovascular benefit was observed when the treated patient attained a serum uric acid concentration below 6 mg/dl (p. 9).
Accordingly, before the effective filing date of the claimed invention, the art taught both (1) the precise urate-lowering treatment regimen of White in subjects already having cardiovascular disease; and (2) that allopurinol-mediated urate lowering to concentrations below 6 mg/dl was associated with decreased acute myocardial infarction risk.
Regarding claim 2 –
White expressly identifies its major cardiovascular endpoint as a composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent coronary revascularization, i.e., substantially the same cardiovascular events recited in claim 2. Larsen additionally teaches that allopurinol treatment was associated with reduced incidence of a cardiovascular composite consisting of myocardial infarction, stroke, and cardiovascular death, while Rodriguez-Martin teaches reduces acute myocardial infarction risk associated with allopurinol treatment and attainment of serum urate below 6 mg/dl.
Regarding claim 3 –
White expressly reports that approximately half its cardiovascular disease/gout population was above 65 years of age or older (p. 1204, Table 1).
Regarding claim 4 –
White expressly teaches administering allopurinol to cardiovascular disease subjects that have a BMI of less than 30 kg/m2 (p. 1208).
Regarding claim 5 –
White expressly teaches administration of febuxostat to cardiovascular disease patients with diastolic blood pressure of 78 mmHg (p. 22, Table S5 of Supplementary Index).
Regarding claim 6 –
White expressly enrolled cardiovascular disease patients having a history of stroke who received either febuxostat or allopurinol (p. 1208).
Regarding claim 7 –
White expressly enrolled cardiovascular disease patients having serum uric acid >7 mg/dl who received either febuxostat or allopurinol (p. 1208).
Regarding claims 8 and 9 –
White expressly enrolled cardiovascular disease patients having gout who received either febuxostat or allopurinol (p. 1200).
Regarding claim 10 –
White teaches administration of allopurinol in amounts from 200 mg to 600 mg/day depending on renal function and serum urate response (p. 1203). These dosages fall entirely within and substantially span the claimed 100-600 mg/day range.
Regarding claim 11 –
White teaches administration of febuxostat between 40 to 80 mg/day, with dosage selected according to serum urate response (p. 1200).
Regarding claim 13 –
White teaches the following febuxostat titration protocol:
Patients who were randomly assigned to receive febuxostat initially received 40 mg/day and continued to receive this dose if the serum urate level was less than 6.0 mg/dl after 2 weeks of therapy; and
If the patient’s serum urate level was higher than 6.0 mg/dl at the week 2 visit, the dose of febuxostat was increased to 80 mg once daily for the remainder of the trial (p. 1201).
It therefore would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to employ White’s allopurinol treatment regimen in a hyperuricemic patient having cardiovascular disease for the additional purpose of reducing the patient’s acute myocardial infarction risk, while titrating treatment to attain serum urate levels below 6 mg/dl. One of ordinary skill would be motivated to do so because Larsen and Rodriguez-Martin provided reason to expect that such urate-lowering treatment would reduce cardiovascular events. The skilled artisan would have a reasonable expectation of success because White had already demonstrated that allopurinol could be safely administered and titrated to the claimed serum urate target in thousands of patients having established cardiovascular disease, while Larsen and Rodriguez-Martin provided clinical evidence associating allopurinol therapy and attainment of low serum urate levels with improved cardiovascular outcomes as it related to acute myocardial infarction. This combination would have involved use of a known urate-lowering regimen in a known patient population to obtain a cardiovascular benefit already suggested by the clinical literature.
Claims 12 is rejected under 35 U.S.C. 103 as being unpatentable over White, Larsen, and Rodriguez-Martin as applied to claims 1-11 and 13 above, and as evidence by Chatoth (“The Stages of Chronic Kidney Disease,” published: 01 February 2021).
The teachings of White, Larsen, and Rodriguez-Martin are previously discussed.
Regarding claim 12 –
White teaches essentially the same renal function-dependent allopurinol titration protocol:
Doses of allopurinol were modified according to kidney function;
Patients with an estimated creatinine clearance of at least 60 ml/min initially received allopurinol at a dose of 300 mg/day; and
The 300 mg daily dose was increased in 100 mg increments monthly until the patient either had a serum urate level of less than 6.0 mg/dl or was receiving an allopurinol dose of 600 mg once daily (p. 1201).
Patients with an estimated creatinine clearance of at least 30 but less than 60 ml/min initially received 200 mg of allopurinol;
The 200 mg daily dose was increased in 100 mg increments until the patient either had a serum urate level of less than 6.0 mg/dl or was receiving an allopurinol dose of 400 mg once daily (pp. 1201-02).
Thus, the claimed doses, renal function thresholds, titration increments, serum-urate endpoint, and maximum doses were each disclosed by White.
White expresses renal function as estimated creatinine clearance using the Cockcroft-Gault formula (p. 1204), whereas claim 12 expresses the corresponding renal function as eGFR. However, as evidence by Chatoth, White’s creatinine clearance values directly correspond to the claimed eGFR values. White indicates a creatinine clearance value of 60 ml/min or more indicated stage 1 or stage 2 chronic kidney disease and a value of at least 30 but less than 60 ml/min indicated stage 3 chronic kidney disease (p. 1204). Chatoth demonstrates stage 1 and stage 2 chronic kidney diseases correspond to an eGFR above 60 ml/min/1.73 m2 and stage 3 chronic kidney disease corresponds to an eGFR value of 30-59 ml/min/1.73 m2 (p. 1 and 2). Therefore, as evidenced by Chatoth, the creatinine clearance values of White directly correspond to the eGFR values claimed by applicant in claim 12.
Both creatinine clearance and eGFR were conventional clinical estimates of renal filtration used to classify kidney function, diagnose chronic kidney disease, and guide drug dosing. Substitution of one routinely used renal function estimate for another to identify patients falling within corresponding renal function categories would have been a predictable clinical implementation, particularly because the reason for stratification in White was simply to modify allopurinol dosage according to renal function.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Co-pending application 18/836,184
Claims 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 18/836,184 (‘184), and in further view of White and Larsen (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘184, while directed to the treatment of chronic kidney disease, recites a nearly identical protocol as the instantly claimed method. The claims of ‘184 make obvious the instantly claimed invention because the prior art established that the same urate-lowering agents – particularly allopurinol and febuxostat – were administered to hyperuricemic patients having cardiovascular risk and were investigated for cardiovascular event reduction.
White administered allopurinol or febuxostat to 6,190 subjects having gout and expressly teaches gout is a chronic illness characterized by hyperuricemia and is associated with an increased risk of cardiovascular and chronic kidney diseases (p. 1201). Furthermore, White expressly enrolled subjects with stage 1, 2, or 3 chronic kidney disease (p. 1204). Thus, White provides an express link between hyperuricemia, cardiovascular disease, and chronic kidney disease. Furthermore, Larsen studied hyperuricemic populations having serum urate concentrations of at least 6 mg/dl and found that allopurinol treatment was associated with a decreased risk of a cardiovascular composite comprising myocardial infarction, stroke, or cardiovascular death.
Accordingly, one of ordinary skill in the art, starting with the claimed CKD method of ‘184, would have found it obvious to use the same xanthine oxidase inhibitors/urate-lowering method in a hyperuricemic patient having cardiovascular disease to arrive at the instantly claimed method. One of ordinary skill would have found it obvious because the prior art expressly taught administration of those same agents in hyperuricemic cardiovascular populations and supplied reason to associate urate-lowering therapy, particularly allopurinol therapy, with cardiovascular risk reduction. The substitution of the cardiovascular indication for the CKD indication of ‘184 therefore represents an obvious variation of an otherwise substantially identical claimed urate-lowering method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claim 1 is objected to. Claims 1-13 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
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/JULIA A. ROSSI/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
1 Lee et al. Cited by applicant in 20 February 2026 IDS as: “Rapid reduction in uric acid by a urate-lowering agent is associated with recurrent cardiovascular events.” Published 13 April 2020.
2 Brucato et al. “Management of hyperuricemia in asymptomatic patients: A critical appraisal.” Published: 15 January 2020.
3 Culleton et al. “Serum Uric Acid and Risk for Cardiovascular Disease and Death: The Framingham Heart Study.” 06 July 1999.
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