DETAILED ACTION
Status of the Claims
Claims 116, 118-120, 122-129 and 132-134 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The instant Application is a Continuation of U.S. Application No. 18/818,714, filed August 29, 2024, which is a Continuation of U.S. Application No. 15/456,520, filed March 11, 2017, which claims the benefit of priority under 35 U.S.C. § 119 of United States provisional Application Nos. 62/307,412 filed March 11, 2016; 62/339,944 filed May 22, 2016; 62/346,348 filed June 6, 2016; 62/397,832 filed September 21, 2016; 62/398,422 filed September 22, 2016; 62/403,664 filed October 3, 2016; 62/430,547 filed December 6, 2016; and 62/442,948 filed January 5, 2017.
The U.S. effective filing date has been determined to be 10/03/2016, the filing date of the Application No.62/403,664. Applicant's claim for priority to prior filed Applications (see above) is acknowledged, however the examiner does not find support for the patient class “a subject with an elevated serum uric acid level and/or undesired uric acid deposits or a subject identified as having had or being expected to have gout flare” (instant claim 116, line 2) in the prior filed Applications.
Information Disclosure Statement
The information disclosure statement submitted on 12/10/2025 was filed after the mailing date of the first office action on the merits however Applicant has indicated the appropriate fee has been apaid. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 116, 118-120, 122-129 and 132-134 remain rejected under 35 U.S.C. 103 as being unpatentable over MALDONADO (US 2014/0328854; published November, 2014). in view of FRASER (US 2012/0276134; published November, 2012); Fiorino et al.1 (“A single Cohort, Dose Escalation Phase 1 Study of Intravenous Infusion of Pegsiticase (Formerly Uricase-PEG 20), A Drug For Managing Hyperuricemia In Refectory Gout” 2010, Arthritis & Rheumatism, Vol. 62, Supplement 10, DOI: 10.1002/art.27913. 2 pages); Sundy et al.2 (“Reduction of Plasma Urate Levels Following Treatment With Multiple Doses of Pegloticase (Polyethylene Glycol–Conjugated Uricase) in Patients With Treatment-Failure Gout - Results of a Phase II Randomized Study,” 2008, Arthritis & Rheumatism Vol. 58, No. 9, pp 2882–2891) and Garay et al. (“Immunogenicity of Polyethylene Glycol (PEG),” 2011; The Open Conference Proceedings Journal, Vol. 2, pp. 104-107).
Applicants Claims
Applicant claims a method, comprising sequentially administering, via intravenous infusion, to a subject with an elevated serum uric acid level and/or undesired uric acid deposits or a subject identified as having had or as being expected to have gout flare (1) a composition comprising synthetic nanocarriers comprising poly(D,L-lactide)(PLA) and poly(D,L-lactide)-poly(ethylene glycol)(PLA-PEG) comprising rapamycin, at a dose of 0.15 mg/kg rapamycin with each administration and (2) a composition comprising pegsiticase at a dose of 0.2 mg/kg with each administration, wherein the composition comprising synthetic carriers and the composition comprising pegsiticase are sequentially administered monthly for at least three months, wherein the composition comprising synthetic nanocarriers is administered prior to the composition comprising pegsiticase with each sequential administration, and wherein the composition comprising pegsiticase is administered within one hour of administering the composition comprising synthetic nanocarriers with each sequential administration (instant claim 116).
Claim interpretation: The instant Specification defines: “‘Concomitantly’ means administering two or more materials/agents to a subject in a manner that is correlated in time, preferably sufficiently correlated in time so as to provide a modulation in a physiologic or immunologic response, and even more preferably the two or more materials/agents are administered in combination. In embodiments, concomitant administration may encompass administration of two or more materials/agents within a specified period of time, preferably within 1 month, more preferably within 1 week, still more preferably within 1 day, and even more preferably within 1 hour. In embodiments, the two or more materials/agents are sequentially administered. In embodiments, the materials/agents may be repeatedly administered concomitantly; that is concomitant administration on more than one occasion.” (paragraph bridging pp. 16-17).
Determination of the scope
and content of the prior art (MPEP 2141.01)
MALDONADO teaches tolerogenic synthetic nanocarriers and therapeutic macromolecules for reduced or enhanced pharmacodynamic effects (title) “compositions and methods that provide pharmacodynamic effects specific to therapeutic macromolecules. The effects may result from reduced doses of therapeutic macromolecules in combination with immunosuppressant doses. The effects may also be enhanced with such compositions.” (abstract, see whole document). And further that: “This invention relates to immunosuppressant doses, in some embodiments attached to synthetic nanocarriers that are administered concomitantly with a therapeutic macromolecule, and related methods. The compositions and methods allow for efficient pharmacodynamic effects specific to the therapeutic macromolecule. The compositions and methods provided can, therefore, be used to generate pharmacodynamic responses in a subject even at reduced doses of the therapeutic macromolecule. The compositions and methods provided herein can also be administered repeatedly concomitantly to generate desired pharmacodynamic and immunologic effects.” ([0002]).
MALDONADO teaches that “In preferred embodiments, the synthetic nanocarriers comprise a polymer as provided herein. These synthetic nanocarriers can be completely polymeric or they can be a mix of polymers and other materials.” ([0124]). And further that: “In some embodiments, the polymer comprises a polyester, polycarbonate, polyamide, or polyether, or unit thereof. In other embodiments, the polymer comprises poly(ethylene glycol) (PEG), polypropylene glycol, poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), or a polycaprolactone, or unit thereof. In some embodiments, it is preferred that the polymer is biodegradable.” ([0127]). MALDONADO discloses Example 1 including PLGA in combination with PLA-PEG and rapamycin ([0217]-[0219]) nanoparticles produced by a water-in-oil emulsion process ([0221]-[0222])(instant claim 116, PLA/PLA-PEG synthetic nanocarriers).
MALDONADO teaches that “Therapeutic treatments, such as protein or enzyme replacement therapies, often result in undesired immune responses to the particular therapeutic. In such cases, cells of the immune system recognize the therapeutic as foreign and attempt to neutralize or destroy it, just as they attempt to destroy infecting organisms such as bacteria and viruses. Such undesired immune responses can neutralize the efficacy of the therapeutic treatment or cause hypersensitive reactions to the therapeutic. These undesired responses may be reduced through the use of immunosuppressant drugs.” ([0003]).
MALDONADO teaches that “In one aspect, a method comprising providing an immunosuppressant dose, wherein in some embodiments the immunosuppressant dose is attached to synthetic nanocarriers, and administering a reduced pharmacodynamically effective dose of a therapeutic macromolecule concomitantly with the immunosuppressant dose to a subject is provided.” ([0004]). And particularly that: “In another aspect, a method comprising providing therapeutic macromolecules that cause or are expected to cause anti-therapeutic macromolecule antibodies upon repeated dosing in one or more subjects; and providing an immunosuppressant dose, wherein the immunosuppressant dose is attached to synthetic nanocarriers. In some embodiments, the method comprises repeatedly dosing at the same or a lower dose a subject with the therapeutic macromolecules concomitantly with the immunosuppressant dose. In some embodiments, the concomitant administration is according to a protocol that has been demonstrated to result in maintenance of a pharmacodynamic effect of the therapeutic macromolecule over two or more doses of the therapeutic macromolecule to a subject.” ([0007]). And further including “a composition or kit comprising a reduced pharmacodynamically effective dose of a therapeutic macromolecule for use in any one of the methods provided herein is provided in combination with an immunosuppressant dose wherein in some embodiments the immunosuppressant is attached to synthetic nanocarriers.” ([0010]).
MALDONADO teaches that: “In one embodiment of any one of the methods or compositions or kits provided, the immunosuppressant dose comprises a statin, an mTOR inhibitor […]. In another embodiment of any one of the methods or compositions or kits provided, the mTOR inhibitor is rapamycin.” ([0015]). And that: “In one embodiment of any one of the methods or compositions or kits provided, the therapeutic macromolecule comprises a therapeutic protein.” - “In another embodiment of any one of the methods or compositions or kits provided, the infusible or injectable therapeutic protein comprises […] pegloticase, pegsiticase […].” - “In another embodiment of any one of the methods or compositions or kits provided, the enzymes comprise KRYSTEXXA (pegloticase).” [emphasis added]([0016])(instant claim 116, pegsiticase). MALDONADO teaches that: “FIG.10 shows anti-KRYSTEXXA antibody titers in mice that were treated with KRYSTEXXA with or with nano-carriers attached to rapamycin.” ([0034]). And particularly Example 8 - Evaluating Responses to KYSTEXXA including that: “A control group of C57BL/6 age-matched (5-6 weeks) female were injected i.v. in the tail vain with PBS while the treated group was injected with 0.9 mg of nanocarriers attached to rapamycin (Nanocarrier ID 1, 2 or 3) in combination with 40 μg of KRYSTEXXA on days -21 and -14. All animals received weekly injections from day 0 to day 28 of l00 μg of KRYSTEXXA combined to 20 μg of CpG s.c. in the hind limb (d0, 7, 12, 28). The control animals develop an immune response against KRYSTEXXA that can be measured by the anti-KRYSTEXXA IgM antibody titers. The results in FIG. 10 show that treating animals with synthetic nanocarriers administered concomitantly with KRYSTEXXA in the same solution were effective in preventing antibody formation to KRYSTEXXA for a prolonged period of time. The treated animals did not develop an anti-KRYSTEXXA response even after five injections of KRYSTEXXA+CpG without the nanocarriers.” [emphasis added]([0316]). And further that: “The data show that the administration of immunosuppressant attached to synthetic nanocarriers with KRYSTEXXA can reduce the anti-KRYSTEXXA antibody response, and such a reduction can remain even after being administered KRYSTEXXA subsequent to the nanocarrier treatment with a strong adjuvant. This demonstrates the reduction of an undesired immune response against a protein with concomitant administration of immunosuppressant attached to synthetic nanocarriers. Finally, the results support that a protocol was established as provided herein.” [emphasis added]([0317]). As the examiner understand the prior art, pegloticase and pegsiticase are both PEGylated uricases but are not identical. However, given the disclosure of both pegloticase and pegsiticase by MALDONADO, the pegloticase (KRYSTEXXA) being exemplified in combination with rapamycin in combination, the substitution of pegsiticase would have been prima facie obvious as an obvious variant as taught by MALDONADO ([0016]). Specifically regarding the disclosure of “nanocarriers attached to rapamycin,” MALDONADO discloses that: “ In embodiments, encapsulation is a form of attaching.” [emphasis added]([0064])(instant claim 118). MALDONADO further defines “Concomitantly” consistent with the definition of the instant Specification (discussed above) in paragraph [0079].
MALDONADO further teaches that: “Examples of infusion therapy or injectable therapeutic proteins include, for example, […] pegloticase (Savient Pharmaceuticals/Krystexxa™), pegsiticase […].” ([0191])(instant claim 116, pegsiticase).
Regarding the limitation “wherein the composition comprising synthetic nanocarriers and the composition comprising pegsiticase are administered monthly for at least three months.” (instant claim 116, lines 8-9), MALDONADO discloses that “Amount effective” includes: “Therefore, in some embodiments, an amount effective is any amount of a composition or dose provided herein (or multiple compositions or doses as provided herein) that produces one or more of the desired pharmacodynamic effects, therapeutic effects and/or immune responses as provided herein.” [emphasis added]([0054]). And that: “In some embodiments of any one of the methods provided, the amount effective is one in which the desired response persists in the subject for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or longer. In other embodiments of any of the compositions and methods provided, the amount effective is one which produces a measurable desired response for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or longer.” ([0056])(instant claim 116, co-administered monthly for at least three months; instant claim 128 – at least four months, five months). The examiner notes that MALDONADO discloses HUMIRA/adalimumab administered with nanocarriers attached to rapamycin weekly for 7 weeks followed by three injections of HUMIRA/adalimumab alone ([0323] - [0324])(instant claim 129), thereby clearly teaching repeated concomitantly administering consistent with the teaching in paragraph [0056] (also see, Figure 19 and Example 22 - Method to Maintain Efficacy of a Biologic Drug During a Period of Multidosing).
MALDONADO teaches that: “In some embodiments, the pharmacodynamic effect is reducing the production of an undesired molecule. In some embodiments, the pharmacodynamic effect is increasing degradation of an undesired molecule, for example uric acid crystals. In some embodiments, the pharmacodynamic effect is an activity of an enzyme.” ([0196])(instant claim 1, “a subject with an elevated serum uric acid level and/or undesired uric acid deposits”). The examiner notes that gout is generally understood to be caused by an elevated level of uric acid resulting in uric acid crystal deposits in the joints resulting in joint pain (arthritis), therefore MALDONADO fairly suggest treating gout in disclosure of paragraph [0196], and particularly taken with the teaching of the therapeutic proteins include uricases ([0183]-[0184]), and particularly the species pegloticase (KRYSTEXXA) and pegsiticase ([0183], [0191])(instant claims 122-126).
Regarding the mean of the particle size distribution obtained by using dynamic light scattering (instant claims 119, 132-133), MALDONADO teaches that: “Preferably, a minimum dimension of at least 75%, preferably at least 80%, more preferably at least 90%, of the synthetic nanocarriers in a sample, based on the total number of synthetic nanocarriers in the sample, is greater than 110 nm, more preferably greater than 120 nm, more preferably greater than 130 nm, and more preferably still greater than 150 nm.” with an aspect ratio encompassing 1:1, and further “Preferably, a maximum dimension of at least 75%, preferably at least 80%, more preferably at least 90%, of the synthetic nanocarriers in a sample, based on the total number of synthetic nanocarriers in the sample is equal to or less than 3 μm, more preferably equal to or less than 2 μm, more preferably equal to or less than 1 μm, more preferably equal to or less than 800 nm, more preferably equal to or less than 600 nm, and more preferably still equal to or less than 500 nm.” and that “Measurement of synthetic nanocarrier dimensions (e.g., effective diameter) may be obtained, in some embodiments, by suspending the synthetic nanocarriers in a liquid (usually aqueous) media and using dynamic light scattering (DLS) ( e.g., using a Brookhaven ZetaPALS instrument).” including the mean of particle size distribution ([0094]). Therefore, MALDONADO fairly defines a range of less than 500 nm and greater than 150 nm as the preferred mean of a particle size distribution (instant claims 119, 132-133).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of MALDONADO is that MALDONADO does not expressly teach: the specific doses in mg/kg, or the weight percent load of the rapamycin in the synthetic nanocarriers (instant claims 120 & 132).
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO (see whole document).
FRASER teaches that: “In another embodiment, the subject has or is at risk of having an undesired immune response against a therapeutic protein that is being administered or will be administered to the subject.” ([0010] & [0036]).
FRASER teaches that: “In another embodiment, the immunosuppressants comprise a statin, an mTOR […]. In another embodiment, the mTOR inhibitor is rapamycin or a rapamycin analog.” ([0013]). FRASER teaches that: “In general, doses of the immunosuppressants and/or antigens in the compositions of the invention can range from about 10 μg/kg to about 100,000 μg/kg. In some embodiments, the doses can range from about 0.1 mg/kg to about 100 mg/kg. In still other embodiments, the doses can range from about 0.1 mg/kg to about 25 mg/kg, […].” ([0070])(instant claim 116, amount of rapamycin (0.15 mg/kg is within the range of the disclosed amount of FRASER, MPEP §2144.05 - “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”).
FRASER teaches that the “‘Load’ of the immunosuppressant or antigen is the amount of the immunosuppressant or antigen coupled to a synthetic nanocarrier based on the total weight of materials in an entire synthetic nanocarrier (weight/weight). […] In yet another embodiment,] the load of the immunosuppressant and/or antigen is between 0.01 % and 20%. In a further embodiment, the load of the immunosuppressant and/or antigen is between 0.1 % and 10%. In still a further embodiment, the load of the immunosuppressant and/or antigen is between 1 % and 10%. […] the load of the immunosuppressant and/or the antigen is 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% on average across a population of synthetic nanocarriers.” ([0103])(instant claims 120 & 134).
FRASER teaches that: “Examples of infusion therapy or injectable therapeutic proteins include, for example […] pegloticase (Savient Pharmaceuticals/Krystexxa™) […].” ([0212]).
FRASER teaches administration of the synthetic nanocarriers prior to administration of the therapeutic protein ([0230])(instant claim 117). FRASER teaches that: “In some embodiments of any of the compositions and methods provided, the amount effective is one in which the desired immune response persists in the subject for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 5 years, or longer.” ([0068])(instant claims 127-128).
Fiorino et al. teaches that: “The enzyme uricase, found in most mammals but not humans, metabolizes uric acid into the highly soluble allantoin and represents a potential treatment for patients suffering from tophaceous and refractory gout. As a foreign protein, uricase is highly immunogenic and not suited for chronic use. Pegsiticase is a pegylated recombinant uricase designed to have an extended half life and reduced that has been previously studied as a single intramuscular dose in a phase 1 study in gout patients. It has not yet been studied as an intravenous agent.” [emphasis added](p. 1, §Background).
Fiorino et al. discloses that: “This was an open label, single dose escalation phase 1 study in healthy volunteers and gout patients. Subjects of age 40-75 with screening plasma uric acid >= 6 mg/dl for men and >=5 mg/dl for women were eligible to participate. The study enrolled five cohorts (4 subjects per cohort) at doses of 0.05, 0.1, 0.2, 0.3, and 0.4 mg/kg, respectively. Pegsiticase was administered via intravenous infusion over one hour without premedication, and subjects were followed for 24 days. The primary endpoint was safety and tolerability and the secondary endpoints were pharmacodynamics (plasma uric acid), and pharmacokinetics (serum uricase activity). Adverse events were graded according to the Common Toxicity Criteria for Rheumatology, version 2.0.” [emphasis added](p. 1, §Methods)(instant claim 116, amount of pegsiticase dose - 0.2 mg/kg).
Sundy et al. teaches that: “Urate production and excretion are normally balanced in humans. However, underexcretion and/or overproduction of urate may lead to elevated urate concentrations in extracellular fluid. When concentrations of urate exceed the saturation limit (~6.8 mg/dl), deposition of urate crystals may occur, resulting in the clinical manifestations of gout, which include attacks of acute arthritis and ultimately chronic arthropathy, tophus formation, or urate nephropathy. (p. 2883, col. 1, 1st paragraph). And further that: “The generally accepted goal of therapy is to reduce serum urate concentrations to <6 mg/dl, which has been demonstrated to reduce the frequency of gout attacks and the size of tophi.” (p. 2883, col. 1, 2nd paragraph).
Sundy et al. teaches that: “We have developed a genetically engineered, recombinant, polyethylene glycol (PEG)–conjugated mammalian uricase ([…]) to control the consequences of hyperuricemia in patients with treatment-failure gout.
Results of 2 phase I studies, involving single subcutaneous or intravenous (IV) injections of PEG-conjugated uricase (pegloticase) demonstrated that this agent rapidly lowered and maintained serum urate levels at <6.0 mg/dl for a 2–3 week period. The object of the present study was to assess the efficacy and safety of multiple doses of pegloticase in patients with treatment-failure gout.” [emphasis added](p. 2883, col. 1, last paragraph)(instant claims 121-126). Sundy et al. teaches that: “This was a 12–14-week randomized, open-label, multicenter, parallel-group study of multiple doses and dose regimens of pegloticase, administered by IV infusion in patients with hyperuricemia and treatment-failure gout.” (p. 2883, col. 2, §Interventions). And particularly that: “Patients were randomized to 1 of 4 pegloticase treatment regimens: 4 mg every 2 weeks or 8 mg every 2 weeks for a total of 6 doses, or 8 mg every 4 weeks or 12 mg every 4 weeks for a total of 3 doses. Pegloticase (4 mg/ml) was packaged in single-use glass vials with a rubber injection stopper, filled to deliver 1 ml of study drug. For dosing, the drug was diluted in 100 ml phosphate buffered saline (PBS) and administered by IV infusion over a period of 30 minutes.” [emphasis added](p. 2883, col. 2, last paragraph through p. 2884, col. 1, 1st paragraph; paragraph 2885, Table 1)(instant claim 116, “pegsiticase are administered monthly for at least three months.”).
Sundy et al. teaches that: “In 31 patients (76%), at least 1 serum sample was positive for antipegloticase immunoreactivity following administration of the initial dose.” And that: “As shown in Table 3, the presence of antibody was associated with a shortened circulating half-life of pegloticase and an increased area under the curve for urate.” (p. 2888, col. 2, §Antibody to pegloticase).
Garay et al. teaches that: “Covalent attachment of polyethylene glycol (PEG) to active proteins (PEGylation technology) successfully generated several FDA-approved compounds, including four blockbusters, which are considered non immunogenic. However, PEG antibodies and intolerance to the infusion were reported in some patients with gout treated with pegloticase, a PEG-uricase recently approved by the FDA (Food and Drug Administration, USA). […] Animal studies clearly showed that PEG-uricases and some other PEGylated proteins might elicit antibody formation against PEG. This anti-PEG response can accelerate the clearance of PEGylated proteins. […] In conclusion, pre-existing or newly developed PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEGylated proteins in some patients. The immunogenicity of PEGylated therapeutic agents in clinical use or development deserves to be re-examined by investigating PEG antibodies.” (abstract).
Garay et al. teaches that: “Pegloticase (Krystexxa®, Savient Pharmaceuticals, USA) a polyethylene glycol (PEG) conjugate of a porcine-like uricase, was recently approved by the FDA (Food and Drug Administration, USA) for the treatment of chronic gout, refractory or intolerant to conventional therapy. Placebo controlled, 6-month clinical trials showed that pegloticase, at doses of 8 mg every 2 weeks, induced a significant decrease in plasma uric acid, associated with the dissolution of tophi in 40% of patients at final visit (45% in patients treated for 25 weeks). However, 58% of the patients were non-responders (according to the criteria of plasma urate <360 μM for 80% of the time), which correlated with the formation of anti-pegloticase antibodies and intolerance to the infusion (see also [6]). This was a surprising result because PEG-protein conjugates are widely regarded as immunologically safe.” (p. 104, col. 1, 1st paragraph). Garay et al. further teaches that: “Because of the medical importance of gout and the relative success of pegloticase, research efforts should be dedicated to investigate the immunogenicity of other PEG uricases in development, such as pegsiticase and to reduce uricase immunogenicity.” (p. 106, col. 1, 3rd paragraph). And further that: “In conclusion, pre-existing or newly developed PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEGylated proteins in some patients. The immunogenicity of PEGylated therapeutic agents in clinical use or development deserves to be re-examined by investigating PEG antibodies.” (p. 106, col. 1, last paragraph).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of a subject with elevated uric acid level such as a gout patient with a composition comprising a PEGylated uricase, such as pegsiticase, and a composition comprising nanocarriers containing rapamycin, as suggested by MALDONADO and FRASER, and particularly in view of the teaching of immune response reducing efficacy of the PEGylated uricase pegloticase, as suggested by Sundy et al. and Garay et al., in order to reduce the immune response, thereby increasing the efficacy of the PEGylated uricase in patients, the dose of the PEGylated uricase and the nanocarriers containing rapamycin being effective for the same, which encompasses pegsiticase at 0.2 mg/kg and nanocarriers containing rapamycin in the range of about 0.1 mg/kg to about 25 mg/kg, as suggested by Fiorino et al. and FRASER, respectively, and the treatment frequency being monthly for at least three months, as suggested by Sundy et al. for effective reduction of uric acid levels (treatment of gout).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the prior art teaches methods of administering rapamycin loaded nanocarriers (particularly biodegradable polyesters), and teaches treating elevated uric acid levels (gout) with PEGylated uricases. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 12/10/2025 have been fully considered but they are not persuasive.
Applicant argues that: “Specifically, none of the cited references, alone or in combination, teach or suggest the claimed combination of doses, frequency, and timing of administration of the specific synthetic nanocarriers and pegsiticase. The claims are directed, among other things, to a method of sequentially administering, via intravenous infusion, to a subject with an elevated serum uric acid level and/or undesired uric acid deposits or a subject identified as having had or as being expected to have gout flare, synthetic nanocarriers comprising poly(D,L lactide) (PLA) and poly(D,L lactide) poly(ethylene glycol) (PLA-PEG) and comprising rapamycin, at a dose of 0.15 mg/kg rapamycin with each administration and pegsiticase at a dose of 0.2 mg/kg with each administration, wherein the composition comprising synthetic nanocarriers and the composition comprising pegsiticase are sequentially administered monthly for at least three months, wherein the composition comprising synthetic nanocarriers is administered prior to the composition comprising pegsiticase with each sequential administration, and wherein the composition comprising pegsiticase is administered within one hour of administering the composition comprising synthetic nanocarriers with each sequential administration.” (p. 6, 2nd paragraph). And that: “First, it is noted that the ordinarily skilled person would not have combined the cited references to arrive at the claimed invention. In particular, the teachings of the references do not disclose or suggest many of the features of the claims, including the sequential administration of the first composition (comprising synthetic nanocarriers and rapamycin) and the second composition (comprising pegsiticase), such sequential administration occurring within one hour, along with the doses, timing, and frequency, for these specific compositions. As Dr. Traber notes, "this application provides the first demonstration that pegsiticase can be used with a drug that induces immune tolerance (e.g., synthetic nanocarriers comprising rapamycin) to treat gout in humans effectively." (paragraph bridging pp. 6-7).
In response the examiner argues that MALDONADO clearly does teach sequential administration occurring within one hour – specifically they teach: “"Concomitantly" means administering two or more materials/agents to a subject in a manner that is correlated in time, preferably sufficiently correlated in time so as to provide a modulation in a physiologic or immunologic response, and even more preferably the two or more materials/agents are administered in combination. In embodiments, concomitant administration may encompass administration of two or more materials/agents within a specified period of time, preferably within 1 month, more preferably within 1 week, still more preferably within 1 day, and even more preferably within 1 hour.” [emphasis added]([0079]). And further that: “The data show that the administration of immunosuppressant attached to synthetic nanocarriers with KRYSTEXXA can reduce the anti-KRYSTEXXA antibody response, and such a reduction can remain even after being administered KRYSTEXXA subsequent to the nanocarrier treatment with a strong adjuvant. This demonstrates the reduction of an undesired immune response against a protein with concomitant administration of immunosuppressant attached to synthetic nanocarriers. Finally, the results support that a protocol was established as provided herein.” ([0317]). Additionally, the definition of “Concomitantly” in the instant Specification is the same as in MALDONADO with the addition of “In embodiments, the two or more materials/agents are sequentially administered.” which is defined as “In embodiments, concomitant administration may encompass administration of two or more materials/agents within a specified period of time, […] even more preferably within 1 hour.” (instant claim 116, last three lines).
Regarding the frequency “wherein the composition comprising synthetic nanocarriers and the composition comprising pegsiticase are sequentially administered monthly for at least three months” (instant claim 116, lines 7-9), MALDONADO discloses that “Amount effective” includes: “Therefore, in some embodiments, an amount effective is any amount of a composition or dose provided herein (or multiple compositions or doses as provided herein) that produces one or more of the desired pharmacodynamic effects, therapeutic effects and/or immune responses as provided herein.” [emphasis added]([0054]). And that: “In some embodiments of any one of the methods provided, the amount effective is one in which the desired response persists in the subject for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or longer. In other embodiments of any of the compositions and methods provided, the amount effective is one which produces a measurable desired response for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or longer.” ([0056])(instant claim 116, sequentially administered monthly for at least three months; instant claim 128 – at least four months, five months). MALDONADO teaches that: “In embodiments, the materials/agents may be repeatedly administered concomitantly, that is concomitant administration on more than one occasion, such as may be provided in the Examples.” [emphasis added]([0079]).
Applicant argues that: “Pegloticase and pegsiticase (pegadricase) are not interchangeable, and the teachings with respect to one enzyme will not necessarily translate to the other. Dr. Traber states: "I respectfully disagree with the Examiner's assertion that the two enzymes are 'obvious variants' of one another (Office Action, p. 23). The two are structurally different: pegloticase is recombinant mammalian uricase derived from a porcine-like source and conjugated to 10 strands of 10-kDa monomethoxypolyethylene glycol (PEG),2 whereas pegsiticase comprises multiple 20 kilodalton molecules of PEG and is derived from Candida utilis.3 I further note that pegsiticase is very immunogenic."4 Dr. Traber goes on to describe the immunogenicity of both enzymes, noting that in early studies while pegloticase/KRYSTEXXA could be administered to patients on a repeated biweekly basis, pegsiticase was found to be too immunogenic and could only be administered a single time. The two enzymes also differ in that they elicit different immune responses, as antibody responses against pegloticase are directed to the polyethylene glycol portion of the molecule, whereas antibody responses against pegsiticase are directed to the uricase protein itself. According to Dr. Traber, "in my experience, I would not expect that teachings relating to dosage and timing of administration of pegloticase/KRYSTEXXA administration to be applicable to pegsiticase. Thus, it is my opinion that the treatments relating to pegloticase/KRYSTEXXA of the cited references could not be simply extrapolated to such a different enzyme (pegsiticase) with different properties." As the two enzymes are very different from one another, one of ordinary skill in the art would not reasonably extend the findings with one to the other, especially with respect to dosing regimens. Thus, the teachings of Sundy and Maldonado with respect to pegloticase are not relevant with respect to pegsiticase.” (paragraph bridging pp. 7-8).
Firstly, the examiner notes that the Declaration is an opinion declaration, and the examiner previously stated that: “As the examiner understand the prior art, pegloticase and pegsiticase are both PEGylated uricases but are not identical. However, given the disclosure of both pegloticase and pegsiticase by MALDONADO, the pegloticase (KRYSTEXXA) being exemplified in combination with rapamycin in combination, the substitution of pegsiticase would have been prima facie obvious as an obvious variant as taught by MALDONADO ([0016]). Specifically regarding the disclosure of “nanocarriers attached to rapamycin,” MALDONADO discloses that: “ In embodiments, encapsulation is a form of attaching.” ([0064])(instant claim 118). MALDONADO further defines “Concomitantly” consistent with the definition of the instant Specification (discussed above) in paragraph [0079].” Additionally the examiner cites WO 2014/179771 which is has the same inventive entity as MALDONADO (same inventors and Applicant), and discloses the same subject matter as [0016] in MALDONADO with the addition that: “In another embodiment of any one of the methods or compositions provided herein, the enzymes comprise KRYSTEXXA (pegloticase) or pegsiticase.” [emphasis added] (p. 4, lines 12-13) which is a more explicit disclosure of the “pegloticase, pegsiticase” alternatives taught by MALDONADO ([0016]). The examiner agrees that pegloticase and pegsiticase are not the same and are structurally distinct, however, the issues is whether one of ordinary skill would have considered using pegsiticase before the effective filing date of the claimed invention in combination with the nanocarriers comprising rapamycin taught by MALDONADO.
The examiner maintains that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of a subject with elevated uric acid level such as a gout patient with a composition comprising a PEGylated uricase, such as pegsiticase, and a composition comprising nanocarriers containing rapamycin, as suggested by MALDONADO and FRASER, and particularly in view of the teaching of immune response reducing efficacy of the PEGylated uricase pegloticase, as suggested by Sundy et al. and Garay et al., in order to reduce the immune response, thereby increasing the efficacy of the PEGylated uricase in patients, the dose of the PEGylated uricase and the nanocarriers containing rapamycin being effective for the same, which encompasses pegsiticase at 0.2 mg/kg and nanocarriers containing rapamycin in the range of about 0.1 mg/kg to about 25 mg/kg, as suggested by Fiorino et al. and FRASER, respectively, and the treatment frequency being monthly for at least three months, as suggested by Sundy et al. for effective reduction of uric acid levels (treatment of gout).
Applicant argues that: “With respect to Fiorino, the teachings provide only a single dose of pegsiticase and not repeated administrations as claimed. In addition, of the four doses tested, it was the highest dose (0.4 mg/kg) that was found to maintain plasma uric acid levels at or near the limit of detection. Dr. Traber notes that "if I arguendo were to combine the teachings of Sundy and Fiorino with nothing more, the result would still not be the claimed method.” (p. 8, 2nd paragraph).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “Further, with respect to the claimed dose of rapamycin (0.15 mg/kg), it is noted that Fraser describes doses of immunosuppressants and/or antigens spanning three orders of magnitude and ranging from 10 μg/kg to 100,000 μg/kg. There is no specific teaching of 15 μg/kg (0.15 mg/kg) rapamycin let alone a suggestion that such a dose would be therapeutically efficacious administered as claimed. In fact, Dr. Traber states that "based on pegsiticase being potentially more immunogenic than pegloticase, I would likely have selected a larger dose of rapamycin, in order to counteract the immunogenicity of the enzyme." Additionally, it is noted that rapamycin has been approved as sirolimus protein-bound particles for intravenous use at a dose of 100 mg/m2 (FYARRO™) which is approximately 2.7 mg/kg. Accordingly, the claimed dose is significantly lower than that which would have been expected to work in combination with pegsiticase, if one of skill in the art were to attempt such a combination arguendo.” (p. 8, 3rd paragraph).
In response the examiner argues that both do dose of the rapamycin and the dose of the pegsiticase are within the scope of what is taught in the cited prior art and are therefore not considered inventive in the context of the rejected claims. FRASER teaches that: “In another embodiment, the immunosuppressants comprise a statin, an mTOR […]. In another embodiment, the mTOR inhibitor is rapamycin or a rapamycin analog.” ([0013]). FRASER teaches that: “In general, doses of the immunosuppressants and/or antigens in the compositions of the invention can range from about 10 μg/kg to about 100,000 μg/kg. In some embodiments, the doses can range from about 0.1 mg/kg to about 100 mg/kg. In still other embodiments, the doses can range from about 0.1 mg/kg to about 25 mg/kg, […].” ([0070])(instant claim 116, amount of rapamycin (0.15 mg/kg is within the range of the disclosed amount of FRASER, MPEP §2144.05 - “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”). And Fiorino et al. discloses that: “This was an open label, single dose escalation phase 1 study in healthy volunteers and gout patients. Subjects of age 40-75 with screening plasma uric acid >= 6 mg/dl for men and >=5 mg/dl for women were eligible to participate. The study enrolled five cohorts (4 subjects per cohort) at doses of 0.05, 0.1, 0.2, 0.3, and 0.4 mg/kg, respectively. Pegsiticase was administered via intravenous infusion over one hour without premedication, and subjects were followed for 24 days. The primary endpoint was safety and tolerability and the secondary endpoints were pharmacodynamics (plasma uric acid), and pharmacokinetics (serum uricase activity). Adverse events were graded according to the Common Toxicity Criteria for Rheumatology, version 2.0.” [emphasis added](p. 1, §Methods)(instant claim 116, amount of pegsiticase dose - 0.2 mg/kg; instant claim 130).
Additionally, MALDONADO teaches that: “Amounts effective can involve reducing the level of an undesired immune response, although in some embodiments, it involves preventing an undesired immune response altogether. Amounts effective can also involve delaying the occurrence of an undesired immune response. An amount that is effective can also be an amount that produces a desired therapeutic endpoint or a desired therapeutic result. In other embodiments, the amounts effective can involve enhancing the level of a desired response, such as a therapeutic endpoint or result. Amounts effective, preferably, result in a tolerogenic immune response in a subject to an antigen, such as a therapeutic macromolecule. The achievement of any of the foregoing can be monitored by routine methods.” [emphasis added]([0055]). And further that: “Amounts effective will depend, of course, on the particular subject being treated; the severity of a condition, disease or disorder; the individual patient parameters including age, physical condition, size and weight; the duration of the treatment; the nature of concurrent therapy (if any); the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.” [emphasis added]([0057])
Applicant further argues that: “Further, the combination of cited references does not teach or suggest sequentially administering synthetic nanocarriers comprising rapamycin followed by pegsiticase intravenously within an hour and repeating the administration monthly for at least three months. The Examiner has cobbled together cherry-picked passages from the cited references to try to demonstrate that the claimed administration protocol is in the art, instead of viewing the invention as a whole.” (p. 8, 4th paragraph).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “sequentially administering synthetic nanocarriers comprising rapamycin followed by pegsiticase intravenously”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The examiner particularly notes that instant claim 116 requires sequentially administering but dose not specify the sequence argued.
Applicant argues that: “There is no reasonable expectation of success based on the combined teachings of the cited references. Instead, Garay and Sundy relate to pegloticase; Fiorino describes administration of a single dose of pegsiticase alone; and Maldonado and Fraser describe synthetic nanocarriers comprising rapamycin generally with an example in Maldonado being specific to pegloticase. There is no reason, and the Examiner has not provided one, why one of ordinary skill in the art would have had a reasonable expectation of success in undertaking the claimed methods.” (p. 9, 2nd paragraph). And that: “Instead, as described in the Traber declaration, there are a number of reasons why the result of the claimed methods was not predictable from the teachings of the cited references. As is noted above, pegloticase and pegsiticase are different enzymes with different properties and that elicit different immune responses. Accordingly, they are not obvious variants of one another. In addition, pegsiticase is very immunogenic having been found in early studies to be too immunogenic to be administered to patients more than one time. Thus, results with pegloticase simply could not have been extended to pegsiticase. Moreover, references such as Garay teach away from using a more immunogenic enzyme like pegsiticase. Further, with respect to the dose of rapamycin, the claimed dose is significantly lower than what would have been expected to work in combination with pegsiticase. The teachings of the cited references, which were summarized above, provide no results or demonstrations that would lead one of ordinary skill in the art to predict the outcome of using the specific compositions, specific doses, and specific administration regimen of the claimed methods. On the contrary, there were a number of reasons why there was no predictability based on the teachings of the cited references.” (p. 9, 3rd paragraph).
MPEP §2143.02 makes clear that: “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention.” And “Conclusive proof of efficacy is not required to show a reasonable expectation of success.” And further that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness.” And the relevant time for obviousness analysis under the AIA , the relevant time is "before the effective filing date of the claimed invention."
In the instant case MALDONADO clearly suggest that: “This invention relates to immunosuppressant doses, in some embodiments attached to synthetic nanocarriers that are administered concomitantly with a therapeutic macromolecule, and related methods. The compositions and methods allow for efficient pharmacodynamic effects specific to the therapeutic macromolecule. The compositions and methods provided can, therefore, be used to generate pharmacodynamic responses in a subject even at reduced doses of the therapeutic macromolecule. The compositions and methods provided herein can also be administered repeatedly concomitantly to generate desired pharmacodynamic and immunologic effects.” ([0002]). Where the “immunosuppressant” is rapamycin and the “therapeutic macromolecule” is pegsiticase the clear intention of the invention of MALDONADO is to reduce immunogenic response to the therapeutic macromolecule by concomitantly – “As undesired immune responses that are generated during therapeutic treatment with therapeutic macromolecules can be counteracted with the methods, compositions or kits provided […].” ([0051], also see [0049]-[0050]). Given the fact that MALDONADO teaches the immunosuppressant is rapamycin and the therapeutic molecule is pegsiticase, one of ordinary skill would have had a reasonable expectation of success that the rapamycin-nanocarrier (immunosuppressant) composition would reduce the undesired immune response to pegsiticase (therapeutic macromolecule).
In response to Applicant’s suggestion that Garay teach away from using a more immunogenic enzyme like pegsiticase, Garay et al. further teaches that: “Because of the medical importance of gout and the relative success of pegloticase, research efforts should be dedicated to investigate the immunogenicity of other PEG uricases in development, such as pegsiticase and to reduce uricase immunogenicity.” (p. 106, col. 1, 3rd paragraph). Which is clearly consistent with MALDONADO teaching reducing immune response to a therapeutic macromolecule such as a pegsiticase composition by concomitant administration of an immunosuppressant such as a rapamycin-nanocarrier composition.
Applicant further argues that: “Third, a prima facie case of obviousness may be rebutted by unexpected results. As is outlined in paragraphs 22-26 of the Traber Declaration, there were a number of surprising results stemming from the claimed methods. In the application, the number of flares per patient month were compared between different treatments, and it was found that the flare frequency is reduced to 0.04 flares per patient month when synthetic nanocarriers comprising rapamycin are administered with pegsiticase, compared to flare frequencies of 0.77 (pegloticase biweekly), and 0.90 (pegloticase monthly) (Table 4). This finding was particularly surprising, as urate-lowering therapies were known to cause an initial increase in gout flares. In addition, it was found that sequential administration of polymeric synthetic nanocarriers comprising rapamycin with pegsiticase significantly reduced induction of uricase-specific anti-drug antibodies administered monthly for at least three months in non-human primates (FIG. 3 of the published application). Post-filing data has consistently demonstrated the same findings discovered by the instant inventors. For instance, the reduction in gout flares is further illustrated in a 2025 poster where the claimed administration regimens reduced gout flares (FIGs. 3-5). In particular, FIG. 3 of the poster demonstrates that there is a decrease or plateau in patients' gout flare incidence during weeks 21-24 of treatment, and over 90% of patients were flare-free, whereas the placebo group experienced an increase (up to 22.4% of patients) in gout flare incidence over the same time period. Methods of the claims "reduced ADA formation, prolonged uricase activity, and reduced levels of sUA in adults with symptomatic gout and hyperuricemia" over a 6 month treatment period. In contrast, "only 42 % of pegloticase-treated patients maintain sUA control (sUA < 6 mg/dl) after 6 months."” (paragraph bridging pp. 9-10).
In response the examiner argues that MALDONADO clearly teaches “In one embodiment, the concomitant administration is according to a protocol that has been demonstrated to enhance a pharmacodynamic effect of the therapeutic macromolecule upon concomitant administration with the immunosuppressant dose, as compared to administration of the therapeutic macromolecule when not administered concomitantly with the immunosuppressant dose, and each in the presence of an anti-therapeutic macromolecule antibody response.” [emphasis added]([0005]). Wherein a therapeutic macromolecule is disclosed as pegsiticase and the immunosuppressant is disclosed as rapamycin, including with a synthetic nanocarrier composition. Therefore, one of ordinary skill would have expected an enhanced pharmacodynamic effect of pegsiticase (therapeutic macromolecule) when concomitantly administered with PLA-PEG nanocarriers encapsulating the immunosuppressant drug rapamycin.
Arguendo the results were considered unexpected, such results should be commensurate with the claimed invention, where claim 116 is not limited to gout patients (see instant claims 124-126), or any gout “flare frequency”. MPEP §716.02 teaching that: “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.”
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Applicant further argues that: “Fourth, the claimed methods represent a solution for a long felt, but unsolved, need. As Dr. Traber explains that "until the discoveries described in the instant application, treatment with uricases, such as KRYSTEXXA, faced significant challenges due to the formation of ADAs" and that the patient population at the time was known to be a difficult population to treat with effective therapies lacking. Dr. Traber further notes "[n]ot until the studies performed by the instant inventors could one of ordinary skill recognize what treatment regimen with pegsiticase would provide durable serum uric acid control with long-term treatment."”
MPEP §716.04 makes clear that: (1) Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. (2) Second, the long-felt need must not have been satisfied by another before the invention by the inventor. And (3) Third, the invention must in fact satisfy the long-felt need. Based on the teachings of MALDONADO et al. the alleged long felt need was satisfied by MALDONADO et al. Additionally, pegloticase and pegsiticase were known treatments for gout, and though they may have had problems with immune response, it clearly would have been an alternative treatment known before the time of the instantly claimed invention.
Response to Applicant’s 37 CFR 1.132 declaration filed 12/10/2025:
The examiner has fully considered Applicant’s declaration and does not find it presents a convincing basis for patentability as the declaration is an opinion declaration by Applicant which does not include data comparing to the closest prior art or closer (MPEP §716.01(c), 716.02(d)). For example Applicant cites SEL-212 as “a method of the claims” but does not appear to be commensurate with the claims.
Claims 116, 118-120, 122-129 and 132-134 remain rejected under 35 U.S.C. 103 as being unpatentable over MALDONADO (US 2014/0328854; published November, 2014) in view of FRASER (US 2012/0276134; published November, 2012); Fiorino et al. (“A single Cohort, Dose Escalation Phase 1 Study of Intravenous Infusion of Pegsiticase (Formerly Uricase-PEG 20), A Drug For Managing Hyperuricemia In Refectory Gout” 2010, Arthritis & Rheumatism, Vol. 62, Supplement 10, DOI: 10.1002/art.27913. 2 pages) and Kishimoto et al. (“Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles,” 01-AUG-2016; Nature Nanotechnology, Vol. 11, pp. 890-899 and supplementary information, 25-pages).
Applicants Claims
Applicant claims are discussed above.
Claim interpretation: As discussed above.
Determination of the scope
and content of the prior art (MPEP 2141.01)
MALDONADO teaches tolerogenic synthetic nanocarriers and therapeutic macromolecules for reduced or enhanced pharmacodynamic effects, as discussed above and incorporated herein by reference.
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO, as discussed above and incorporated herein by reference.
Fiorino et al. teaches that: “The enzyme uricase, found in most mammals but not humans, metabolizes uric acid into the highly soluble allantoin and represents a potential treatment for patients suffering from tophaceous and refractory gout. As a foreign protein, uricase is highly immunogenic and not suited for chronic use. Pegsiticase is a pegylated recombinant uricase designed to have an extended half life and reduced that has been previously studied as a single intramuscular dose in a phase 1 study in gout patients. It has not yet been studied as an intravenous agent.” (p. 1, §Background).
Fiorino et al. discloses that: “This was an open label, single dose escalation phase 1 study in healthy volunteers and gout patients. Subjects of age 40-75 with screening plasma uric acid >= 6 mg/dl for men and >=5 mg/dl for women were eligible to participate. The study enrolled five cohorts (4 subjects per cohort) at doses of 0.05, 0.1, 0.2, 0.3, and 0.4 mg/kg, respectively. Pegsiticase was administered via intravenous infusion over one hour without premedication, and subjects were followed for 24 days. The primary endpoint was safety and tolerability and the secondary endpoints were pharmacodynamics (plasma uric acid), and pharmacokinetics (serum uricase activity). Adverse events were graded according to the Common Toxicity Criteria for Rheumatology, version 2.0.” [emphasis added](p. 1, §Methods)(instant claim 1, amount of pegsiticase dose - 0.2 mg/kg; instant claim 130).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of MALDONADO et al. is that these references do not expressly teach the immunogenic response of pegsiticase.
Kishimoto et al. teaches that: “The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice.” (abstract, see whole document).
Kishimoto et al. teaches that: “Pegloticase (Krystexxa), a pegylated uricase enzyme used to metabolize uric acid for the treatment of refractory gout, induces ADAs in ∼90% of subjects, resulting in the loss of efficacy as well as anaphylactic reactions. Recently, the US Food and Drug Administration (FDA) has advocated that the biopharmaceutical industry take a proactive risk-based approach to reducing and mitigating unwanted immunogenicity. Prevention of the formation of ADAs in an antigen-specific manner would be desirable to reduce late stage clinical failure of promising novel biologics in development and to improve the safety and efficacy of marketed products.” And further that: “Rapamycin was selected as an immunomodulator for its ability to induce tolerogenic dendritic cells in vitro. We have previously shown that nanoparticles containing both rapamycin and an antigen are effective in inducing durable antigen-specific immunological tolerance in vivo. However, for the purpose of inhibiting ADAs, it would be desirable to have a universal approach that can be added onto any biologic therapy without having to optimize the nanoparticle for each specific biologic and without altering the biologic itself, its intended dose route or regimen. Here, we demonstrate that synthetic vaccine particles that contain only rapamycin (SVP-Rapamycin) can be co-administered with any free antigen to induce immunological tolerance. […] The route of administration of the SVP-Rapamycin can be matched to that of the biologic. Injecting pegylated uricase with SVP-Rapamycin intravenously (i.v.) in uricase-deficient mice allowed for repetitive injections of pegylated uricase resulting in a sustained reduction of serum uric acid levels.” (p. 890, paragraphs 1-2).
Kishimoto et al. teaches the Schematic of SVP-Rapamycin with a free antigen as follows:
PNG
media_image1.png
256
214
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Greyscale
(p. 891, Figure 1a).
Kishimoto et al. teaches that: “Next we evaluated the ability of SVP-Rapamycin to inhibit ADAs against pegsiticase, a pegylated uricase. Uricase-deficient mice, which display elevated levels of serum uric acid, were treated with pegsiticase with or without SVP-Rapamycin (Fig. 5a). A single treatment with pegsiticase alone reduced uric acid levels below 6 mg dl, the target threshold for the control of uric acid in gout therapy; however, subsequent injections did not, correlating with the emergence of an anti-uricase IgG response. In contrast, treatment with pegsiticase + SVP-Rapamycin inhibited the ADA response, enabling the sustained maintenance of low serum uric acid levels. Similar results were observed in wildtype animals challenged with a bolus of uric acid (Supplementary Fig. 8). Importantly, treatment with pegsiticase + SVP-Rapamycin also inhibited the ADA response in cynomolgus monkeys (Fig. 5b).” (p. 895, col. 1, 2nd paragraph). And that: “Treatment with pegsiticase + SVP-Rapamycin i.v. prevented the ADA response, allowing for the efficacious control of uric acid levels in uricase-deficient mice (Fig. 5a).” (p. 895, col. 2, §Discussion, lines 20-22). And further that: “Protein pegylation is thought to reduce the immunogenicity of biologics; however, some pegylated enzymes, such as pegylated-uricase and pegylated-asparaginase, are highly immunogenic. We show here that SVP-Rapamycin treatment can inhibit the antibody response to pegylated uricase (Fig. 5).” (p. 879, col 1, line 13 through col. 1, line 2). Kishimoto et al. teaches that: “The translation of SVP-Rapamycin efficacy to humans is currently being tested in combination with a pegylated uricase, a highly immunogenic class of drug, in subjects with hyperuricemia.” (p. 898, col. 1, last three lines).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat a subject with an elevated serum uric acid level such as a gout patient with a PLA/PLA-PEG - rapamycin nanocarrier concomitantly administered with pegsiticase, as suggested by MALDONODO, FRASER and Kishimoto et al., the effective dose of the pegsiticase being 0.2 mg/kg as suggested by Fiorino et al., in order to reduce the immunogenicity of the pegsiticase, as suggested by the cited prior art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because administration of PEGylated uricase for the treatment of gout was well-known prior to the claimed invention, and MALDONODO, FRASER and Kishimoto et al., teach methods of improving the same, by administering rapamycin containing nanocarriers (SVP-Rapamycin) to improve treatment with biologics such as pegsiticase by reducing immune response in the patients treated with the same. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 04/15/2025 have been fully considered but they are not persuasive.
Applicant argues that: “The deficiencies of Maldonado, Fraser, and Fiorino are discussed above. Kishimoto, cited for its purported disclosure of "[PLGA] nanoparticles comprising rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to coadministered proteins" (Office Action, p. 31), does not remedy the deficiencies of Maldonado, Fraser, and Fiorino.” (p. 12, 1st paragraph).
In response Applicants arguments have been addressed herein above.
Applicant further argues that: “Moreover, Kishimoto was published August 1, 2016, after the present application's priority date (March 11, 2016) and therefore, is disqualified as a reference (see, e.g., 35 U.S.C. § 102(a)(l)). If, arguendo, Kishimoto is not disqualified under§ 102(a)(l), Kishimoto is excepted as prior art under 35 U.S.C. § 102(b)(l).” (p. 11, 3rd paragraph).
The Kishimoto et al. reference does list common authors (named inventors: Takashi K. Kishimoto and Lloyd Johnston) but also list many other authors (see reference) therefore for under 35 U.S.C. § 102(b)(l) Applicant should file a 37 C.F.R. 1.130 declaration to establish that a disclosure (Kishimoto et al.) is not prior art in accordance with 35 U.S.C. 102(b) (see, MPEP §717.01). The examiner finds no 37 C.F.R. 1.130 declaration to establish that a disclosure (Kishimoto et al.) is not prior art in accordance with 35 U.S.C. 102(b) in the instant case.
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 116, 118-120, 122-129 and 132-134 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 116-135 of copending Application No. 18/818,714 (hereafter ‘714).
Instant claim 116 is discussed above.
Copending ‘714 claim 116 recites a method, comprising: concomitantly administering to a subject with an elevated serum uric acid level and/or undesired uric acid deposits or a subject identified as having had or as being expected to have gout flare 1) a composition comprising synthetic nanocarriers comprising poly(D,L lactide) (PLA) and poly(D,L lactide) poly(ethylene glycol) (PLA-PEG) and comprising rapamycin, at a dose of 0.05 - 0.5 mg/kg rapamycin with each administration and 2) a composition comprising pegsiticase at a dose of 0.1-1.2 mg/kg with each administration, wherein the composition comprising synthetic nanocarriers and the composition comprising pegsiticase are administered monthly for at least three months. ‘714 claims 117-126 are identical to instant claims 117-126. ‘714 claim 128 encompasses administering a dose of 0.15 mg/kg rapamycin, and claim 130 encompasses administering pegsiticase at a dose of 0.2 mg/kg. ‘714 claims 131-135 are identical to instant claims 131-135.
The difference between the instantly rejected claims and the claims of copending ‘714 is that the claim of copending ‘714 do not expressly limit the dose of rapamycin and pegsiticase in the base claim (116), however, the dependent claims fully encompasses the instantly claimed subject matter.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending ‘714 because the claimed doses broader but the dependent claims make clear that the doses are not different in the instant claims. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in the art to produce the claimed invention from the claims of ‘714.
This is a provisional obviousness-type double patenting rejection.
Claims 116, 118-120, 122-129 and 132-134 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application Nos. 19/448,738 (claims 1-124; hereafter ‘738) and 17/092,148 (claims 1-5, 7, 13, 20, 24, 28, 30-31, 35, 39, 53, 58, 68-69 & 72; hereafter ‘148) in view of MALDONADO (as cited above) FRASER (as cited above) and Fiorino et al. (as cited above).
Instant claim 116 is discussed above.
Copending ‘738 claim 5 recites a method, comprising: concomitantly administering to a subject having an anti-uricase antibody level (e.g.’ a titer) below a threshold, 1) a composition comprising synthetic nanocarriers comprising an immunosuppressant and 2) a composition comprising uricase. ‘738 claim 32 recites “The method of any one of the preceding claims, wherein the composition comprising synthetic nanocarriers comprising an immunosuppressant is administered at a dose of 0.05 - 0.5 mg/kg immunosuppressant with each administration.” ‘738 claim 36 recites “The method of any one of the preceding claims, wherein the composition comprising uricase is administered at a dose of 0.1 - 1.2 mg/kg uricase with each administration.” Claim 49 recites the uricase is pegylated uricase, claim 50 recites the pegylated uricase is pegisiticase or pegloticase. Claims 52-55 recite the immunosuppressat is rapamycin with synthetic nanocarriers, which include PLA and PLA-PEG (claims 57-62). Claim 73-74 require intravenous administration and intravenous infusion, respectively. Claim 31 recites “wherein the composition comprising synthetic nanocarriers comprising an immunosuppressant and the composition comprising uricase are administered monthly for at least three months, four months, five months, six months, seven months, eight months, nine months, ten months or more.”
Copending ‘148 claim 3 recites a method, comprising sequentially co-administering to a subject having, at the time of the initial co-administration, symptomatic chronic gout inadequately controlled with xanthine oxidase inhibitor and a serum uric acid level of > 7 mg/dL 1) a composition comprising polymeric synthetic nanocarriers comprising poly (D,L-lactide) (PLA), poly(D,L-lactide)-poly(ethylene glycol) (PLAPEG), and rapamycin; and 2) a composition comprising pegadricase, wherein the composition comprising polymeric synthetic nanocarriers comprising PLA, PLA-PEG, and rapamycin is administered at a dose of 0.05 mg/kg - 0.3 mg/kg rapamycin and the dose of the composition comprising pegadricase is. 0.1 mg/kg - 0. 5 mg/kg; wherein the composition comprising synthetic nanocarriers is administered prior to the composition comprising pegdricase with each co-administration is administered within one hour of administering the composition comprising synthetic nanocarriers with each co-administration; wherein the subject (a) has three or more gout flares within the past 18 months; and/or (b) has a history of inter-flare intervals of one week or less.
The difference between the instantly rejected claims and the claims of copending ‘153 is that the claim of copending ‘153 do not expressly claim a specific embodiment within the scope of the instantly rejected claims.
The difference between the instantly rejected claims and the claims of copending ‘148 is that the claim of copending ‘148 do not expressly claim administering monthly for at least three months or for ten months or more (instant claims 1, 127-128); administering by intravenous infusion (instant claims 121 & 135); or the size of the nanocarriers (claims 119, 132-133).
MALDONADO teaches tolerogenic synthetic nanocarriers and therapeutic macromolecules for reduced or enhanced pharmacodynamic effects, as discussed above and incorporated herein by reference.
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO, as discussed above and incorporated herein by reference.
Fiorino et al. teaches administering by intravenous infusion of pegsiticase for treatment of hyperuricemia in refractory gout including a dose of 0.2 mg/kg, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending ‘153 and ‘148 because the copending claims are directed at administering PEGylated uricases in conjunction with the immunosuppressant rapamycin in nanocarriers. The skilled artisan would have been motivated to modify the claims of copending ‘153 and/or ‘148 and produce the instantly rejected claim because longer term treatment would have been beneficial for gout patients. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in producing the instantly claimed invention from the copending claims in view of the cited prior art.
This is a provisional obviousness-type double patenting rejection.
Claims 116, 118-120, 122-129 and 132-134 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,426,451 in view of Fiorino et al. (as cited above) and FRASER (as cited above).
Instant claim 116 is discussed above.
‘451 claim 1 recites a method, comprising: concomitantly administering monthly to a subject in need thereof 1) a composition comprising synthetic nanocarriers comprising poly(D,L-lactide) (PLA) and poly(D,L-lactide)-poly(ethylene glycol) (PLA-PEG) and comprising a rapalog and 2) a composition comprising pegadricase; and further comprising administering 3) an anti-inflammatory therapeutic, wherein the anti-inflammatory therapeutic is colchicine or ibuprofen, wherein when the anti-inflammatory therapeutic is colchicine, 1.2 mg colchicine is administered once one week prior to the first concomitant administration of 1) and 2) and subsequently 0.6 mg colchicine is administered once per day, and wherein when the anti-inflammatory therapeutic is ibuprofen, 600 mg ibuprofen is administered three times a day starting one week prior to the first concomitant administration of 1) and 2). The disclosure of ‘451 indicates that “pegylated uricase is pegsiticase (i.e. pegadricase)” (col. 2, lines 24-25), therefore the examiner is reading “pegadricase” as synonymous with pegsiticase (instant claim 1).
The difference between the instantly rejected claims and the claims of ‘451 is that the claim of ‘451 do not expressly claim the dosing or the frequency of administration (i.e. monthly for at least three months).
Fiorino et al. teaches administering by intravenous infusion of pegsiticase for treatment of hyperuricemia in refractory gout including a dose of 0.2 mg/kg, as discussed above and incorporated herein by reference.
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of ‘451 because the claims are directed at administering PEGylated uricase in conjunction with the immunosuppressant rapamycin . The skilled artisan would have been motivated to modify the claims of ‘451 and produce the instantly rejected claim because the frequency and dosing would have provided the best treatment for gout patients for which PEGylated uricases are indicated. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in producing the instantly claimed invention from the copending claims in view of the cited prior art.
Claims 116, 118-120, 122-129 and 132-134 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,194,078 in view of Fiorino et al. (as cited above) and FRASER (as cited above).
Instant claim 116 is discussed above.
‘078 claim 1 recites a method, comprising: concomitantly administering to a subject in need thereof 1) a composition comprising synthetic nanocarriers comprising an immunosuppressant and 2) a composition comprising an uricase; and further comprising administering 3) a composition comprising an anti-inflammatory therapeutic, wherein the composition comprising an anti-inflammatory therapeutic is administered concomitantly with the composition comprising synthetic nanocarriers comprising an immunosuppressant and the composition comprising an uricase, and wherein the concomitant administration of 1), 2), and 3) is repeated on a monthly basis. ‘078 claims 14-15 limit the uricase to pegylated uricases and including pegadricase (pegsiticase), and claims 16-18 limits the immunosuppressant to rapamycin.
The difference between the instantly rejected claims and the claims of ‘078 is that the claim of ‘078 do not expressly claim the species of nanocarriers is PLA/PLA-PEG, administering monthly for at least three months or for ten months or more (instant claims 116, 127-128); administering by intravenous infusion (instant claims 121 & 135); or the size and loading of the nanocarriers (claims 119-120, 132-134).
Fiorino et al. teaches administering by intravenous infusion of pegsiticase for treatment of hyperuricemia in refractory gout including a dose of 0.2 mg/kg, as discussed above and incorporated herein by reference.
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of ‘078 because the claims are directed at administering PEGylated uricase in conjunction with the immunosuppressant rapamycin . The skilled artisan would have been motivated to modify the claims of ‘078 and produce the instantly rejected claim because the frequency and dosing would have provided the best treatment for gout patients for which PEGylated uricases are indicated. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in producing the instantly claimed invention from the copending claims in view of the cited prior art.
Claims 116, 118-120, 122-129 and 132-134 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,553,041 (hereafter ‘041) in view of in view of MALDONADO (as cited above) FRASER (as cited above) and Fiorino et al. (as cited above).
Instant claim 116 is discussed above.
‘041claim 1 recites a method, comprising: sequentially co-administering to a subject having an antiuricase antibody titer level below a threshold a treatment dose comprising: 1) a composition comprising synthetic nanocarriers comprising an immunosuppressant and 2) a composition comprising uricase, wherein the uricase is pegsiticase, wherein the threshold is an anti-uricase antibody titer of 1080 or less, wherein the composition comprising synthetic nanocarriers comprising an immunosuppressant is administered prior to the composition comprising uricase, and wherein the concomitant administering is repeated with a 28 day treatment interval. ‘041 claim 4 recites “The method of claim 1, wherein the method is a method of preventing gout flare, and wherein the subject is not administered an additional therapeutic to prevent gout flare concomitantly with the sequential co-administration. ‘041 claim 7 recites “The method of claim 1, wherein the composition comprising synthetic nanocarriers comprising an immunosuppressant is administered at a dose of 0.05-0.5 mg/kg immunosuppressant with each administration. ‘041 claim 9 recites “The method of claim 1, wherein the composition comprising uricase is administered at a dose of 0.1-1.2 mg/kg uricase with each administration.”
The difference between the instantly rejected claims and the claims of ‘041 is that the claim of ‘041 do not expressly claim the species of immunosuppressant is rapamycin; the synthetic nanocarriers is PLA/PLA-PEG, administering monthly for at least three months or for ten months or more (instant claims 116, 127-128); administering by intravenous infusion (instant claims 121 & 135); or the size and loading of the nanocarriers (claims 119-120, 132-134).
MALDONADO teaches tolerogenic synthetic nanocarriers and therapeutic macromolecules for reduced or enhanced pharmacodynamic effects, as discussed above and incorporated herein by reference.
Fiorino et al. teaches administering by intravenous infusion of pegsiticase for treatment of hyperuricemia in refractory gout including a dose of 0.2 mg/kg, as discussed above and incorporated herein by reference.
FRASER teaches synthetic nanocarrier composition consistent with the disclosure of MALDONADO, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of ‘041 because the claims are directed at administering PEGylated uricase in conjunction with the immunosuppressant of which rapamycin was a known species. The skilled artisan would have been motivated to modify the claims of ‘041 and produce the instantly rejected claim because the frequency and dosing would have provided the best treatment for gout patients for which PEGylated uricases are indicated. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill in producing the instantly claimed invention from the copending claims in view of the cited prior art.
Response to Arguments:
Applicant's arguments filed 12/10/2025 have been fully considered but they are not persuasive.
Applicant suggests that: “Applicant respectfully requests reconsideration in view of the amendments presented herein. Additionally, Applicant notes that a nonstatutory double patenting rejection is based on a comparison of the claims of the application with the claims of the reference patents (or patent applications). For example, MPEP 804 (Il)(B) states that "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)." Applicant respectfully submits that the Office has not established that the claims of the instant application are anticipated or rendered obvious by the claims of the above-referenced patents and patent applications.” (p. 13, 1st paragraph).
In response to Applicants suggestion that “the Office has not established that the claims of the instant application are anticipated or rendered obvious by the claims of the above-referenced patents and patent applications”. 37 CFR 1.111(b) makes clear that: “(b) In order to be entitled to reconsideration or further examination, the applicant or patent owner must reply to the Office action. The reply by the applicant or patent owner must be reduced to a writing which distinctly and specifically points out the supposed errors in the examiner’s action and must reply to every ground of objection and rejection in the prior Office action. The reply must present arguments pointing out the specific distinctions believed to render the claims, including any newly presented claims, patentable over any applied references. If the reply is with respect to an application, a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated.” Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the above-referenced patents and patent applications.
Conclusion
Claims 116, 118-120, 122-129 and 132-134 are pending and have been examined on the merits. Claims 116, 118-120, 122-129 and 132-134 are rejected under 35 U.S.C. 103; and claims are (provisionally) rejected based on the ground of nonstatutory double patenting over claims of USPN 11,426,451; 12,194,078; 12,553,041 and U.S. Application Nos. 18/818,714; 19/448,738; and 17/092,148. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616
1 Cited by Applicant on IDS sheet 29 of 50, last entry.
2 Cited by Applicant on IDS sheet 46 of 50, 10th entry.