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 .
Status of Application, Amendments, And/Or Claims
The Applicants amendments/remarks received 12/23/2025 are acknowledged. Claims 1, 11-15 and 18-20 are amended; claims 2-9 are canceled; claims 21-22 are new; no claims are withdrawn; claims 1 and 10-22 are pending and have been examined on the merits.
Claim Objections
The objection to claims 2-3, as set forth at pp. 2-3 of the previous Office Action, is moot due to cancelation of the claims.
Claim Rejections - 35 USC § 112
The rejection of claims 1-20 under 35 U.S.C. § 112(b), as set forth at pp. 3-6 of the previous Office Action, is moot regarding claims 2-9 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 4-9, 16, 18 and 20 under 35 U.S.C. § 102(a)(1)/102(a)(2) over Zhang et al., US 2014/0065123 (US Patent Application Publication cite 1, IDS, 8/30/2023; herein “Zhang”) as set forth at pp. 6-8 of the previous Office Action, is moot regarding claims 4-9 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
The rejection of claims 1, 4-5, 10, 12-16 and 18-20 under 35 U.S.C. § 102(a)(1)/102(a)(2) over Kent et al., US 2020/0237880 (cite A, PTO-892, 10/1/2025; herein “Kent”) as set forth at pp. 8-9 of the previous Office Action, is moot regarding claims 4-5 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
The rejection of claims 1, 4-10, 16, 18 and 20 under 35 U.S.C. § 102(a)(1)/102(a)(2) over Hartman et al., US 2019/0316097 (cite B, PTO-892, 10/1/2025; herein “Hartman”) as set forth at p. 9 of the previous Office Action, is moot regarding claims 4-9 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1-9, 16, 18 and 20 under 35 U.S.C. § 103(a) over Zhang et al., US 2014/0065123 (US Patent Application Publication cite 1, IDS, 8/30/2023; herein “Zhang”) as set forth at pp. 9-11 of the previous Office Action, is moot regarding claims 2-9 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
The rejection of claims 1-5, 10-16 and 18-20 under 35 U.S.C. § 103(a) over Kent et al., US 2020/0237880 (cite A, PTO-892, 10/1/2025; herein “Kent”) as set forth at pp. 11-12 of the previous Office Action, is moot regarding claims 2-5 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
The rejection of claims 1-10, 16-18 and 20 under 35 U.S.C. § 103(a) over Hartman et al., US 2019/0316097 (cite B, PTO-892, 10/1/2025; herein “Hartman”) as set forth at p. 12 of the previous Office Action, is moot regarding claims 2-9 due to cancelation of the claims and is withdrawn regarding the remaining claims in view of the amendment of the claims.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10-11, 16-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., US 2014/0065123 (US Patent Application Publication cite 1, IDS, 8/30/2023; herein “Zhang”) in view of Hartman et al., US 2019/0316097 (cite B, PTO-892, 10/1/2025; herein “Hartman”).
Zhang teaches urate oxidase preparations comprising a polyethylene glycol-modified urate oxidase and phosphate buffer [0031], wherein the preparation is a pharmaceutical composition [0033] for administration to a subject to treat hyperuricemia (Abst.; [0023]). Zhang teaches that the polyethylene glycol, i.e., PEG, can be 5 kDa monomethoxy PEG (mPEG) modified with N-hydroxysuccinimidyl propionate (SPA), wherein the 5 kDa mPEG-SPA is linked to the urate oxidase via amide linkages ([0015], [0029-30], [0048-50]). Zhang teaches that the coupling of the 5 kDa mPEG-SPA to the urate oxidase is to be performed at a molar ratio of 1:40 to 1:160 (urate oxidase: 5 kDa mPEG-SPA) in 100 mM carbonate buffer, pH 10.3 for 4h at 4 °C [0050].
Zhang teaches that the pharmaceutical compositions of the polyethylene glycol-modified urate oxidase can comprise phosphate buffer and have a pH 7.4 - 9.0 [0033]. Zhang teaches that the PEGylated urate oxidase is PEGylated on the epsilon amino of lysine residues and can comprise 15 PEG molecules conjugated per monomer [0015].
Zhang does not disclose that the urate oxidase comprises the sequence of instant SEQ ID NO: 1, i.e., a chimeric pig/baboon urate oxidase; however, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method of PEGylating urate oxidase with the method of Zhang wherein the urate oxidase comprises a chimeric pig/baboon urate oxidase, i.e., the sequence of instant SEQ ID NO: 1, in view of the disclosure of Hartman.
Hartman teaches urate oxidase preparations comprising a polyethylene glycol-modified urate oxidase and phosphate buffered saline, wherein the preparation is a pharmaceutical composition [0088] for administration to a subject to treat hyperuricemia (Abst.; [0180-185]). Hartman also teaches that the polyethylene glycol, i.e., PEG, can be 5 kDa monomethoxy PEG (mPEG) linked to the urate oxidase via amide linkages ([0098]; Example 5, [0163-166], Table 5). Hartman teaches that the urate oxidase can be SEQ ID NO: 8 [0025], which is 100% identical to instant SEQ ID NO: 1. Hartman demonstrates that the PEGylated urate oxidase can be PEGylated on lysine residues and can comprise 12 PEG molecules conjugated per monomer (Example 5, [0163-166], Table 5). Hartman teaches that the urate oxidase preparation can be in a single-dose form, each dose of the preparation comprising 2-16 mg of pegylated uricase.
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method of Zhang to produce a polyethylene glycol-modified urate oxidase wherein the urate oxidase is SEQ ID NO: 8 of Hartman, which is 100% identical to instant SEQ ID NO: 1 and would have found it obvious to produce compositions of said produced polyethylene glycol-modified urate oxidase comprising phosphate buffer with a pH of 7.4 because Zhang teaches pharmaceutical compositions of the polyethylene glycol-modified urate oxidase comprising phosphate buffer and having pH 7.4. The method of Zhang for conjugating 5 kDa mPEG-SPA to urate oxidase to produce polyethylene glycol-modified urate oxidase [0050] is methodologically indistinguishable from the instant method (specification, [0108]). Both methods comprise incubating the urate oxidase and 5 kDa PEG-SPA at the appropriate molar ratio in a 100 mM carbonate buffer, pH ~10, at ~ 4 °C for > 1h; hence, practicing the method made obvious by Zhang with the urate oxidase made obvious by Hartman (Hartman SEQ ID NO: 8 which is 100% identical to instant SEQ ID NO: 1) would produce a polyethylene glycol-modified urate oxidase wherein at least 11 of the following amino acid sites in the urate oxidase have PEG modifications: K3, K4, K35, K76, K97, K112, K116, K120, K152, K222, K231, K266 and K285, and the amino acid sites are positioned based on an amino acid sequence set forth as SEQ ID NO: 1; wherein the urate oxidase has an amino acid sequence set forth as SEQW ID NO: 1; wherein polyethylene glycol used for the PEG modifications is a N-succinimidyl propionate PEG with a molecular weight of 5 kD: and wherein a modification feed molar ratio of urate oxidase to polyethylene glycol ranges from 1:55 to 1:95. Zhang teaches pharmaceutical compositions of the polyethylene glycol-modified urate oxidase comprising phosphate buffer and having pH 7.4; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to produce a urate oxidase preparation comprising said polyethylene glycol-modified urate oxidase in phosphate buffer with pH 7.4; therefore, claims 1, 10-11, 16, 18 and 21 are prima facie obvious.
Regarding claim 17, Hartman teaches that the urate oxidase preparation can be in a single-dose form, each dose of the preparation comprising 2-16 mg of pegylated uricase; therefore, claim 17 is prima facie obvious.
Regarding claim 20, Zhang teaches administering the preparation to treat hyperuricemia (Abst.; [0023]); hence, a person of ordinary skill in the art at the time of filing would have found it obvious to administer the preparation made obvious by Zhang in view of Hartman to treat hyperuricemia; therefore, claim 20 is prima facie obvious.
Claims 1 and 10-22 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Hartman and Kent et al., US 2020/0237880 (cite A, PTO-892, 10/1/2025; herein “Kent”).
The discussion of Zhang and Hartman regarding claims 1, 10-11, 16-18 and 20-21 set forth in the rejection above is incorporated herein.
Zhang recites that the pharmaceutical compositions of polyethylene glycol-modified urate oxidase can comprise excipients [0012] wherein the excipients can be buffers of phosphate and the pH is 7.4 - 9.0 [0033] but does not specifically teach the limitations of claims 12-15 drawn to the excipients of the composition; however, a person of ordinary skill in the art at the time of filing would have found it obvious for the compositions of the polyethylene glycol-modified urate oxidase in phosphate buffer to meet the limitations of claims 12-15 in view of the disclosure of Kent.
Kent teaches urate oxidase preparations comprising a polyethylene glycol-modified urate oxidase and phosphate buffer, wherein the preparation is a pharmaceutical composition for administration to a subject to treat hyperuricemia (Abst.; [0033-41]).
Kent teaches that the composition can comprise 8 mg PEGylated uricase protein, 2.18 mg Na2HPO4, 0.43 mg NaH2PO4 and 8.77 mg NaCl [0033]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride; therefore, instant claim 10 is prima facie obvious.
Kent teaches that the mass ratio of uricase to buffer reagent is 8 mg : (2.18 mg + 0.43 mg + 8.77 mg) = 8:11.38, i.e., 6:9. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; therefore, instant claim 12 is prima facie obvious.
Kent teaches that the mass ratio of uricase to phosphate is 8 mg : (2.18 mg + 0.43 mg) = 8:2.61, i.e., 6:2. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the phosphate of 6:2; therefore, instant claim 13 is prima facie obvious.
Kent teaches that the mass ratio of uricase to NaCl is 8 mg : 8.77 mg, i.e., 6:6.58. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of uricase to NaCl of 6:7; therefore, instant claim 14 is prima facie obvious.
Kent teaches that the mass ratio of phosphate to sodium chloride is (2.18 mg + 0.43 mg) : 8.77 mg = 2.61:8.77, i.e., 6:20. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of phosphate to sodium chloride of 6:20; therefore, instant claim 15 is prima facie obvious.
Kent teaches that the administration can further comprise mycophenolate mofetil [0039]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to further comprise an additional drug for treating or preventing hyperuricemia; therefore, instant claim 19 is prima facie obvious.
Regarding claim 22, as discussed above, Kent teaches a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; and it is known that the ionic strength of a preparation can affect the stability, i.e., retention of activity, of an enzyme in the preparation; hence, the ionic strength of the PEGylated urate oxidase preparation is a result effective variable which would need to be optimized, for example, to optimize the stability of the enzyme in the preparation. Therefore, a person of ordinary skill in the art would have found it obvious, at the time of the invention, to optimize the mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent, starting with Kent’s ratio of 6:9, to arrive at a mass ratio of 6:10; therefore, instant claim 22 is prima facie obvious. See also MPEP 2144.05 II.A. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%)".
Response to Arguments
Applicant's arguments filed 12/23/2025 have been fully considered but they are not persuasive. Arguments of the Applicant’s Response on pp. 5-11 regarding the claim objections and rejections under 35 U.S.C. §§ 112, 102 and 103 are moot as the rejections have been withdrawn.
Regarding Applicant’s pre-emptive arguments regarding the obviousness of the instant claims over the combination of Zhang, Hartman and Kent set forth on pp. 7-11 of the Response:
As set forth in the rejection above, Zhang teaches methods of producing a polyethylene glycol-modified urate oxidase comprising coupling 5 kDa mPEG-SPA (mPEG modified with N-hydroxysuccinimidyl propionate) via amide linkage to the lysines of the urate oxidase, comprising 15 PEG molecules conjugated per monomer, by coupling 5 kDa mPEG-SPA to the urate oxidase at a molar ratio of 1:40 to 1:160 (urate oxidase: 5 kDa mPEG-SPA) in 100 mM carbonate buffer, pH 10.3 for 4h at 4 °C, which is methodologically indistinguishable from the method (specification, [0108]) used to produce the polyethylene glycol-modified urate oxidase of the instant claims wherein at least 11 of the following amino acid sites in the urate oxidase have PEG modifications: K3, K4, K35, K76, K97, K112, K116, K120, K152, K222, K231, K266 and K285.
Hence, it is prima facie obvious that practicing the method of Zhang with the urate oxidase disclosed in Hartman would produce the polyethylene glycol-modified urate oxidase recited in the instant claims because the method of Zhang is methodologically indistinguishable from the method of the instant claims for producing the polyethylene glycol-modified urate oxidase.
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In the Remarks, p. 7, Applicant alleges that the prior art does not use the same PEG modifier. This is incorrect, Zhang couples 5 kDa PEG-SPA to the urate oxidase. Succinimidyl propionate IS N-succinimidyl propionate; hence, the allegation that the prior art does not use the same PEG modifier is incorrect.
On p. 10, Applicant argues that Zhang teaches an enzyme retention activity of 87.7% (Table 1) while the instant polyethylene glycol-modified urate oxidase retains as high as 100% activity. In response, it is pointed out that enzyme activity retention for the instant invention when a molar ratio of 1:150 (urate oxidase: 5 kDa-PEG-SPA) was used was 88%; Zhang’s retention of 88% activity was with a molar ratio of 1:120 (urate oxidase: 5 kDa-PEG-SPA); hence, it would appear that Zhang’s enzyme activity retention is the same, unsurprisingly, because the same method of coupling with the same reagents is used.
Applicant does not compare the instant results to the enzyme activity of polyethylene glycol-modified urate oxidase produced by Zhang’s method wherein the molar ratio is between 1:56 to 1:94; hence, a proper comparison with the prior art to establish a secondary consideration based on unexpected results has not been met.
Regarding Applicant’s arguments about lysines conjugated per molecule (p. 10), it is noted that the canine urate oxidase used in Zhang has an asparagine at K97 and an arginine at K285 so the canine urate oxidase has 2 less modifiable lysines than the chimeric pig/baboon urate oxidase of instant SEQ ID NO: 1.
Thus, Applicant’s arguments that the claims are not obvious over the combination of Zhang, Hartman and Kent is unpersuasive and the allegation of a secondary consideration based on unexpected results is unpersuasive.
As stated above, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 10-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10 and 16 of copending Application No. 17/521898 (herein “’898”) in view of Kent.
Claim 1 of ‘898 recites a polyethylene glycol-modified urate oxidase, wherein at least 11 of the following amino acid sites in the urate oxidase have PEG modifications: K3, K4, K35, K76, K97, K112, K116, K120, K152, K222, K231, K266 and K285; wherein the amino acid sites are positioned based on an amino acid sequence set forth as SEQ ID NO: 1; wherein the urate oxidase has an amino acid sequence set forth as SEQ ID NO: 1; wherein polyethylene glycol used for the PEG modification is a N-succinimidyl propionate PEG with a molecular weight of 5 kD; and wherein a modification feed molar ratio of urate oxidase to polyethylene glycol ranges from 1:55 to 1:95; claim 8 of ‘898 recites the polyethylene glycol-modified urate oxidase according to claim 1, wherein the urate oxidase has an amino acid sequence set forth as SEQ ID NO: 1, and the polyethylene glycol-modified urate oxidase has the PEG modifications at sites K3, K4, K35, K76, K97, K112, K116, K120, K152, K222, K231, K266 and K285; claim 9 of ‘898 recites a pharmaceutical composition, comprising the urate oxidase according to claim 1; claim 10 of ‘898 recites the pharmaceutical composition according to claim 9, further comprising an additional drug for treatment or prevention of hyperuric acid-related diseases through drug combination; claim 16 of ‘898 recites a method for treating or preventing hyperuric acid-related diseases and reducing a uric acid level in a biological fluid of a subject in need thereof, comprising: administering a therapeutically effective amount of the polyethylene glycol-modified urate oxidase according to claim 1 or a pharmaceutical composition comprising the polyethylene glycol-modified urate oxidase according to claim 1 to the subject.
Claims 1, 8-10 and 16 of ‘898 are silent on excipients for preparations of the produced polyethylene glycol-modified urate oxidase; however, a person of ordinary skill in the art at the time of filing would have found it obvious for the excipients in preparations of the produced polyethylene glycol-modified urate oxidase to comprise a phosphate buffer in view of the disclosure of Kent.
Kent teaches urate oxidase preparations comprising a polyethylene glycol-modified urate oxidase and phosphate buffer, wherein the preparation is a pharmaceutical composition for administration to a subject to treat hyperuricemia (Abst.; [0033-41]).
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for the preparations of the polyethylene glycol-modified urate oxidase made obvious by claims 1 and 8-10 of ‘898 to comprise a phosphate buffer, i.e., a liquid comprising an excipient, the excipient being a buffer reagent wherein the buffer reagent comprises at least one of phosphate or hydrochloride, wherein the buffer reagent comprises at least one selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride; therefore, instant claims 1, 10, 16 and 18-19 are prima facie obvious.
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to administer said preparations to treat hyperuricemia; therefore, instant claim 20 is prima facie obvious.
Kent teaches that the composition can comprise 8 mg PEGylated uricase protein, 2.18 mg Na2HPO4, 0.43 mg NaH2PO4 and 8.77 mg NaCl [0033]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride; therefore, instant claim 10 is prima facie obvious.
Kent teaches that the mass ratio of uricase to buffer reagent is 8 mg : (2.18 mg + 0.43 mg + 8.77 mg) = 8:11.38, i.e., 6:9. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; therefore, instant claim 12 is prima facie obvious.
Kent teaches that the mass ratio of uricase to phosphate is 8 mg : (2.18 mg + 0.43 mg) = 8:2.61, i.e., 6:2. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the phosphate of 6:2; therefore, instant claim 13 is prima facie obvious.
Kent teaches that the mass ratio of uricase to NaCl is 8 mg : 8.77 mg, i.e., 6:6.58. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of uricase to NaCl of 6:7; therefore, instant claim 14 is prima facie obvious.
Kent teaches that the mass ratio of phosphate to sodium chloride is (2.18 mg + 0.43 mg) : 8.77 mg = 2.61:8.77, i.e., 6:20. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of phosphate to sodium chloride of 6:20; therefore, instant claim 15 is prima facie obvious.
Regarding instant claim 17, Kent teaches that the composition can comprise 8 mg PEGylated uricase protein, 2.18 mg Na2HPO4, 0.43 mg NaH2PO4 and 8.77 mg NaCl [0033]; however, the amount of the active dose is a result effective variable which would need to be optimized, for example, for the patient’s weight, age, and disease severity among many variables and a person of ordinary skill in the art would expect the concentration of the active agent to have an obvious effect on parameters such as the effectiveness of treatment. Therefore, a person of ordinary skill in the art would find it obvious to vary this parameter, starting with Kent’s 8 mg, to arrive at the amount of the PEGylated uricase protein that was most efficacious for treating hyperuricemia and would arrive at a unit dose containing 6 mg of the PEGylated uricase; therefore, instant claim 17 is prima facie obvious. See also MPEP 2144.05 II.A. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%)".
Regarding instant claims 11 and 21, it is known that the pH of a preparation can affect the stability, i.e., retention of activity, of an enzyme in a preparation; and Kent discloses phosphate buffered saline compositions similar to the PEGylated urate oxidase composition comprising Na2HPO4, NaH2PO4 and NaCl had a pH of 7.2 [0141]; hence, the pH of the PEGylated urate oxidase preparation is a result effective variable which would need to be optimized, for example, to optimize the stability of the enzyme in the preparation. Therefore, a person of ordinary skill in the art would have found it obvious, at the time of the invention, to optimize the pH, starting with Kent’s pH 7.2, to arrive at a pH of 7.4 to 8.2; therefore, instant claims 11 and 21 are prima facie obvious. See also MPEP 2144.05 II.A.
Regarding claim 22, as discussed above, Kent teaches a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; and it is known that the ionic strength of a preparation can affect the stability, i.e., retention of activity, of an enzyme in the preparation; hence, the ionic strength of the PEGylated urate oxidase preparation is a result effective variable which would need to be optimized, for example, to optimize the stability of the enzyme in the preparation. Therefore, a person of ordinary skill in the art would have found it obvious, at the time of the invention, to optimize the mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent, starting with Kent’s ratio of 6:9, to arrive at a mass ratio of 6:10; therefore, instant claim 22 is prima facie obvious. See also MPEP 2144.05 II.A.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 10-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, 14 and 16 of copending Application No. 18/312166 (herein “’166”) in view of Kent.
Claim 1 of ‘166 recites a method for preparing a polyethylene glycol-modified urate oxidase, characterized by performing a coupling reaction between urate oxidase and polyethylene glycol to obtain the polyethylene glycol-modified urate oxidase, wherein the polyethylene glycol is provided in a form of an acidic solution, and a molar ratio of the urate oxidase to the polyethylene glycol is 1: (56 to 94); claim 8 of ‘166 recites the method according to claim 1, wherein the polyethylene glycol has a molecular weight of not more than 6 KD; or the polyethylene glycol has a monomethoxy group or a hydroxyl group; or the polyethylene glycol is of a linear or branched structure; or the polyethylene glycol is coupled to the urate oxidase via an amide bond; claim 9 of ‘166 recites the method according to claim 1, wherein the polyethylene glycol is a modifying polyethylene glycol, and a modification group of the modifying polyethylene glycol is at least one selected from the group consisting of N-hydroxysuccinimide, N-hydroxysuccinimidyl carbonate, N-hydroxysuccinimidyl acetate, N-hydroxysuccinimidyl propionate, N-hydroxysuccinimidyl butyrate, N-hydroxysuccinimidyl succinate, and bis(p-nitrophenyl) carbonate; claim 10 of ‘166 recites the method according to claim 9, wherein the modification group of the modifying polyethylene glycol is N-hydroxysuccinimide propionate; claim 14 of ‘166 recites the method according to claim 1, wherein at least 11 of the following amino acid sites in the urate oxidase have a PEG modification: T1, K3, K4, K30, K35, K76, K79, K97, K112, K116, K120, K152, K179, K222, K231, K266, K272, K285, K291, K293, wherein the amino acid sites are positioned based on an amino acid sequence set forth as SEQ ID NO: 1; and claim 16 of ‘166 recites the method according to claim 14, wherein the urate oxidase has an amino acid sequence set forth as any one of SEQ ID NOs: 1 to 4. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to use the method set forth in claims 1, 8-10, 14 and 16 of ‘166 to produce a urate oxidase preparation, comprising: an active ingredient, the active ingredient being a polyethylene glycol-modified urate oxidase; wherein at least 11 of the following amino acid sites in the urate oxidase have PEG modifications: K3, K4, K35, K76, K97, K112, K116, K120, K152, K222, K231, K266 and K285, and the amino acid sites are positioned based on an amino acid sequence set forth as SEQ ID NO: 1; wherein the urate oxidase has an amino acid sequence set forth as SEQ ID NO: 1; wherein polyethylene glycol used for the PEG modifications is a N-succinimidyl propionate PEG with a molecular weight of 5 kD: and wherein a modification feed molar ratio of urate oxidase to polyethylene glycol ranges from 1:56 to 1:94.
Claims 1, 8-10, 14 and 16 of ‘166 are silent on excipients for preparations of the produced polyethylene glycol-modified urate oxidase; however, a person of ordinary skill in the art at the time of filing would have found it obvious for the excipients in preparations of the produced polyethylene glycol-modified urate oxidase to comprise a phosphate buffer in view of the disclosure of Kent.
Kent teaches urate oxidase preparations comprising a polyethylene glycol-modified urate oxidase and phosphate buffer, wherein the preparation is a pharmaceutical composition for administration to a subject to treat hyperuricemia (Abst.; [0033-41]).
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for preparations of the produced polyethylene glycol-modified urate oxidase to comprise a phosphate buffer, i.e., a liquid comprising an excipient, the excipient being a buffer reagent wherein the buffer reagent comprises at least one of phosphate or hydrochloride, wherein the buffer reagent comprises at least one selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride; therefore, instant claims 1, 10, 16 and 18 are prima facie obvious.
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to administer said preparations to treat hyperuricemia; therefore, instant claim 20 is prima facie obvious.
Kent teaches that the composition can comprise 8 mg PEGylated uricase protein, 2.18 mg Na2HPO4, 0.43 mg NaH2PO4 and 8.77 mg NaCl [0033]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride; therefore, instant claim 10 is prima facie obvious.
Kent teaches that the mass ratio of uricase to buffer reagent is 8 mg : (2.18 mg + 0.43 mg + 8.77 mg) = 8:11.38, i.e., 6:9. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; therefore, instant claim 12 is prima facie obvious.
Kent teaches that the mass ratio of uricase to phosphate is 8 mg : (2.18 mg + 0.43 mg) = 8:2.61, i.e., 6:2. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of the polyethylene glycol-modified urate oxidase to the phosphate of 6:2; therefore, instant claim 13 is prima facie obvious.
Kent teaches that the mass ratio of uricase to NaCl is 8 mg : 8.77 mg, i.e., 6:6.58. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of uricase to NaCl of 6:7; therefore, instant claim 14 is prima facie obvious.
Kent teaches that the mass ratio of phosphate to sodium chloride is (2.18 mg + 0.43 mg) : 8.77 mg = 2.61:8.77, i.e., 6:20. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to comprise a mass ratio of phosphate to sodium chloride of 6:20; therefore, instant claim 15 is prima facie obvious.
Kent teaches that the administration can further comprise mycophenolate mofetil [0039]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for said preparations to further comprise an additional drug for treating or preventing hyperuricemia; therefore, instant claim 19 is prima facie obvious.
Regarding instant claim 17, Kent teaches that the composition can comprise 8 mg PEGylated uricase protein, 2.18 mg Na2HPO4, 0.43 mg NaH2PO4 and 8.77 mg NaCl [0033]; however, the amount of the active dose is a result effective variable which would need to be optimized, for example, for the patient’s weight, age, and disease severity among many variables and a person of ordinary skill in the art would expect the concentration of the active agent to have an obvious effect on parameters such as the effectiveness of treatment. Therefore, a person of ordinary skill in the art would find it obvious to vary this parameter, starting with Kent’s 8 mg, to arrive at the amount of the PEGylated uricase protein that was most efficacious for treating hyperuricemia and would arrive at a unit dose containing 6 mg of the PEGylated uricase; therefore, instant claim 17 is prima facie obvious. See also MPEP 2144.05 II.A. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%)".
Regarding instant claims 11 and 21, it is known that the pH of a preparation can affect the stability, i.e., retention of activity, of an enzyme in the preparation; and Kent discloses phosphate buffered saline compositions similar to the PEGylated urate oxidase composition comprising Na2HPO4, NaH2PO4 and NaCl had a pH of 7.2 [0141]; hence, the pH of the PEGylated urate oxidase preparation is a result effective variable which would need to be optimized, for example, to optimize the stability of the enzyme in the preparation. Therefore, a person of ordinary skill in the art would have found it obvious, at the time of the invention, to optimize the pH, starting with Kent’s pH 7.2, to arrive at a pH of 7.4 to 8.2; therefore, instant claims 11 and 21 are prima facie obvious. See also MPEP 2144.05 II.A.
Regarding claim 22, as discussed above, Kent teaches a mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent of 6:9; and it is known that the ionic strength of a preparation can affect the stability, i.e., retention of activity, of an enzyme in the preparation; hence, the ionic strength of the PEGylated urate oxidase preparation is a result effective variable which would need to be optimized, for example, to optimize the stability of the enzyme in the preparation. Therefore, a person of ordinary skill in the art would have found it obvious, at the time of the invention, to optimize the mass ratio of the polyethylene glycol-modified urate oxidase to the buffer reagent, starting with Kent’s ratio of 6:9, to arrive at a mass ratio of 6:10; therefore, instant claim 22 is prima facie obvious. See also MPEP 2144.05 II.A.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Regarding the rejection of claims 1-20 on the ground of non-statutory double patenting over claims 1, 7, 9-10 and 16 of copending application 17/521898 in view of Kent, Applicant states (p. 11) “Applicant respectfully requests that the above non-statutory double patenting rejections over co-pending Application No. 17/521898 in view of Kent be held in abeyance until one of the present application and the co-pending application has been granted”. Rejections are not held in abeyance. The rejection is provisional; hence, Applicant is free to amend the claims of 17/521898 or the claims of the instant application so that the claims of 17/521898 do not make obvious the instant claims or to file a terminal disclaimer over the earlier filed application (17/521898). The rejection is maintained with modification to address the amended claims, new claims and for clarity.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Trent R Clarke whose telephone number is (571)272-2904. The examiner can normally be reached M-F 10-7 MST.
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/TRENT R CLARKE/Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651
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