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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed 02/14/2024 has been considered and the references therein are of record.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6-8, 10-14, 17, and 19-20 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Hershfield et al., 2017 (WO2017112826A2) (see instant PTO-892).
The instant claims are drawn to a method of reducing the immunogenicity of a polymer-biologically active agent conjugate, where the conjugate comprises uricase conjugated to about 5 to about 130 POEGMA molecules, where each POEGMA molecule has a poly(methyl methacrylate) (PMM) backbone and side chains of 2 to 9, specifically 2 to 4, monomers of EG repeated in tandem. The instant claims are drawn to the conjugate not inducing an anti-POEGMA antibody response. The instant claims are drawn to each POEGMA molecule independently weighing about 1,000 Da to about 100,000 Da. The instant claims are drawn to the biologically active agent conjugated to the backbone of each POEGMA molecule. The instant claims are drawn to the biologically active agent conjugated to each POEGMA molecule individually through a urethane bond. The instant claims are drawn to each side chain having a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone and the second terminal end comprises an alkyl, ester, amine, amide, or carboxyl group. The instant claims are drawn to each POEGMA molecule functionalized with a hydroxyl group, carboxyl group, carbonate group, amine group, ester group, azide group, alkyne group, or a combination thereof prior to conjugating to the biologically active agent. The instant claims are drawn to the polymer-biologically active agent conjugate having a reduced immune response relative to a polyethylene glycol (PEG)-biologically active agent conjugate having about 5 to about 130 PEG molecules per biologically active agent. Furthermore, the instant claims are drawn to the composition that is used in the method recited above.
Hershfield teaches a molecule-polymer conjugate, wherein the molecule comprises uricase and wherein more than one branched polymer is conjugated to the uricase, wherein the branched polymer is poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and a method of reducing the antigenicity of the uricase by conjugating such branched polymer to the uricase as compared to a PEG-biologically active agent conjugate (claims 1, 18, and 54). Hershfield teaches POEGMA comprises a backbone containing poly (methyl methacrylate) (PMMA) and a plurality of side chains covalently attached to the PMMA backbone (claim 54). Hershfield teaches that each side chain of the POEGMA PMMA backbone comprises from 2 to 9 monomers of ethylene glycol (EG) repeated in tandem (claims 54-60). Hershfield teaches that when more than one POEGMA is conjugated to the molecule, each POEGMA is conjugated to a different site of the molecule selected from the C-terminus, the N-terminus, an internal amino acid, or a combination thereof (claims 16 and 18). In view of the definition of “about” recited in Specification para[0018], the “more than one” recited in claims 16 and 18 is considered to be “about 5”. Hershfield teaches that the uricase is conjugated to the backbone of the branched polymer via a linker (see claims 3, 38-40). Hershfield teaches that each side chain has a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone, and wherein the second terminal end independently comprises an alkyl, ester, amine, amide, or carboxyl group (see claim 4). Hershfield teaches “Krystexxa consists of the tetrameric uricase enzyme (125 kDa total) with 10-11 lysine side-chain amino groups on each of its four subunits reacted with 10 kDa PEG p-nitrophenyl carbonate ester” and that two different individuals developed anti-PEG antibodies during a Phase II clinical trial of Krystexxa (para [000135]). Hershfield teaches that, the oligo(ethylene glycol) side-chains (OEG) of the methyl ether methacrylate backbone in POEGMA are largely responsible for the "stealth" behavior of the polymer and its conjugates, alteration on the side-chain length can thus have an impact on the in vivo behavior of POEGMA conjugates (para[000150]). Since Hershfield teaches the same structure as the claimed conjugate, the claimed conjugate and the conjugate taught by Hershfield would have the same functional characteristics of a reduced immune response relative to a PEG-biologically active agent conjugate having about 5 to about 130 PEG molecules per biologically active agent and it will not induce an anti-POEGMA antibody response. Moreover, Hershfield teaches that the biologically active agent-POEGMA conjugate is not reactive with pre-existing anti-PEG antibodies in a subject, that it will have reduced or eliminated antigenicity, and a reduced immune response (claims 38, 61 & 64; para[0031] & [0083]-[0088]; Example 5). Furthermore, the average molecular weight of each POEGMA will be in the range of about 1000 Da to about 100000 Da given its chemical structure.
Therefore, Hershfield anticipates instant claims 1-4, 6-8, 10-14, 17, and 19-20.
Claim Rejections - 35 USC § 103
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.
Claims 1, 5, 11, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Hershfield et al., 2017 (WO2017112826A2), as applied to claims 1 and 11 above (see instant PTO-892).
Instant claims 1 and 11 are discussed above. Instant claims 5 and 18 are drawn to the conjugate comprising about 25 to about 30 POEGMA molecules per biologically active agent. Instant claim 16 is drawn to each POEGMA molecule individually conjugated to the biologically active agent in a non-site-specific manner.
The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The relevance of Hershfield regarding claims 1 and 11 is set forth above and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Hershfield does not explicitly teach that the conjugate comprises about 25 to about 30 POEGMA molecules per biologically active agent. Hershfield does not explicitly teach each POEGMA molecule being individually conjugated to the biologically active agent in a non-site-specific manner.
The prior art only differs from the claimed invention with respect to the number of POEGMA molecules per biologically active agent. While Hershfield teaches at least two POEGMA molecules per biologically active agent, the instant claims specify the range of about 25 to about 30 POEGMA molecules. The U.S. Court of Customs and Patent Appeals has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention because an ordinary artisan would have found it obvious to optimize the formulation through routine experimentation. An ordinary artisan would have been motivated to optimize the number of POEGMA molecules per biologically active agent to make the most stable and effective composition. MPEP 2144 sets forth Applicant’s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification teaches effective embodiments of the claimed invention with about 5 to about 130 POEGMA molecules per biologically active agent (para[0043]), which is evidence of noncriticality to the claimed invention.
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Hershfield. One of ordinary skill in the art would have found it obvious from Hershfield’s teaching that biologically active agents can be conjugated with POEGMA molecules. While Hershfield specifies that that the POEGMA molecule can be conjugated to specific sites (claim 16 and 18), Hershfield states generally that this conjugation is possible and nowhere specifies that the POEGMA molecules can only be conjugated to specific sites. Logically, an ordinary artisan would find it obvious that the POEGMA molecules can be individually conjugated to the biologically active agent in a non-site-specific manner and an artisan could pick and choose to conjugate the molecules in either a non-site-specific-manner or a site-specific manner in the pursuit of making the optimal conjugate. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims are obvious over the prior art.
Claims 1, 9, 11, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Hershfield et al., 2017 (WO2017112826A2), as applied to claims 1 and 11 above, and in further view of Roberts et al., 2002 (see instant PTO-892).
Instant claims 1 and 11 are discussed above. Instant claims 9 and 15 are drawn to the biologically active agent conjugated to each POEGMA molecule individually through a urethane bond.
The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The relevance of Hershfield regarding claims 1 and 11 is set forth above and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Hershfield does not explicitly teach that the biologically active agent is conjugated to each POEGMA molecule individually through a urethane bond.
Roberts teaches, “Other PEG acylating reagents which produce urethane linked proteins include p-nitrophenyl carbonate (pNPC-PEG in Fig. 1e), trichorophenyl carbonate (TCP-PEG in Fig. 1f) and carbonylimidazole (CDI-PEG in Fig. 1g). These reagents are prepared by reacting chloroformates or carbonylimidazole with the terminal hydroxyl group on mPEG, and these have much lower reactivity than either the SC-PEG or BTC-PEG. Generally, the slower the reaction the more specific the reagent is to certain amino acid groups of the protein. In this way, some selectivity is achieved.”
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Hershfield and Roberts. One of ordinary skill in the art would have arrived at the claimed invention because Roberts teaches that using the reagents chloroformates or carbonylimidazole to link POEGMA to proteins via a urethane bond allows for more site selectivity over which amino acids the ordinary artisan chooses as the site of conjugation. Furthermore, as Roberts teaches that there are multiple reagents which can perform this linkage, it would be obvious to an ordinary artisan that there are various options for conjugating the POEGMA to the peptide from which an ordinary artisan can pick and choose. The person of ordinary skill in the art would have had a reasonable expectation of success based on the disclosures of these prior art references. Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH CESARE whose telephone number is (571)272-6908. The examiner can normally be reached Monday - Friday 10am-4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
Prosecution Insights