Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena without significantly more. The claims recite the natural phenomena of instant SEQ ID NO: 3, which corresponds to residues of the naturally occurring α- chain of the main immunogenic region of the acetylcholine receptor, and instant SEQ ID NO: 5, which corresponds to residues of the naturally occurring α-chain of the T-cell recognition site of the acetylcholine receptor.
Considering the flowchart of subject matter eligibility in MPEP § 2106, the claim is directed to a product, which is a statutory category of invention. (Step 1: YES).
Step 2A, Prong One sets forth the markedly different characteristics analysis that the courts use to identify product of nature exceptions (MPEP 2106.04(c)). The analysis requires determining if the claimed product has "markedly different characteristics from any found in nature". Diamond v. Chakrabarty, 447 U.S. 303, 310, 206 USPQ 193, 197 (1980). The naturally-occurring counterpart to the instant claimed product are the α- chain of the main immunogenic region of the acetylcholine receptor and the α-chain of the T-cell recognition site of the acetylcholine receptor. The only difference between SEQ ID NO: 3 and 5 from their natural counterparts is the addition of a cystine on the C termini to facilitate conjugation to the carrier that is recited in dependent claims. Adding a single cysteine residue to the C-termini to facilitate conjugation does not make the protein markedly different from its natural counterpart as it is a routine, conventional, and well understood activity in the field, as taught by Arumugham et al., 2012 (US8227403B2). Incorporating the product of nature into a pharmaceutical composition does not add a meaningful limitation as it is merely a nominal or token extra-solution component of the claim, and is nothing more than an attempt to generally link the product of nature to a particular technological environment. The claim does not include additional elements that are sufficient to amount to significantly more (also known as an “inventive concept”) than the natural product and are not markedly different than their natural counterparts.
There is no evidence within the specification as filed that the claimed pharmaceutical composition has any structural or functional differences from the naturally-occurring counterparts that amount to a markedly different characteristic. Therefore, claims 1 and 10 are directed to a product that does not markedly differ from the nature-based product, and are not eligible subject matter under 35 U.S.C. 101.
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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Blalock et al., 2007 (WO2007108808-A1) in view of Arumugham et al., 2012 (US8227403B2) (see instant PTO-892).
Instant claims 1-20 are drawn to a pharmaceutical composition, a method of treating myasthenia gravis (MG) in a patient by administering the composition, and a method of making the composition, where the composition comprises one or more peptide epitopes of SEQ ID NOs: 2-5 coupled covalently to either one or more free -NH2 residues, a plurality of free -NH2 residues, at least 4 -NH2 residue, and/or fewer than 20 free -NH2 residues of SEQ ID NO: 1, and where the peptide epitopes are coupled to the carrier protein (SEQ ID NO: 1) via a heterobifunctional crosslinking agent that is reactive for an amine group and a sulphydryl group. The composition comprises 10-1000 micrograms of SEQ ID NO: 3 and/or 10-1000 micrograms of SEQ ID NO:5, as well as a vaccination adjuvant. The instant claims specify that the tryptophan residue at position 8 of SEQ ID NOs: 2-3 is or is not alkylated on the free carbon of its indole group. Claim 8 recites a method for immunization of a patient and claim 9 recites a method of treating MG, both by administering the pharmaceutical composition comprising SEQ ID NO: 3, SEQ ID NO: 5, or a mixture of the two. Instant claims 14-17 and 20 are drawn to a method of making the pharmaceutical composition for use in treating or reducing the likelihood of developing MY, comprising the steps of: first activating the carrier protein SEQ ID NO: 1 with a heterobifunctional crosslinking agent to cause a plurality of -NH2 groups to react with said heterobifunctional crosslinking agent, removing any unincorporated crosslinking agent, coupling one or more of SEQ ID NOs: 2-5 to the activated carrier protein, then separating the peptide epitope-coupled carrier protein from any unreacted substrates and by-products, and then dissolving the peptide epitope-coupled carrier protein in an aqueous solution comprising a buffer so as to ensure a specified pH or lyophilizing the peptide epitope-coupled carrier protein. Instant claim 15 specifies that the heterobifunctional crosslinking agent is reactive for an -NH2 group and an -SH group, and that the one or more peptide epitopes are SEQ ID NOs: 3 or 5. The instant claims specify that the patient is a human, dog, horse, or a member of the camel family. Instant SEQ ID NO: 1 corresponds to CRM197, a mutant of the diphtheria toxin. Instant SEQ ID NO: 2 corresponds to residues 61 to 76 of an α- chain of the main immunogenic region of the acetylcholine receptor. Instant SEQ ID NO: 4 corresponds to residues 100 to 116 of an α-chain of the T-cell recognition site of the acetylcholine receptor. Instant SEQ ID NOs: 2 and 4 differ from SEQ ID NOs: 3 and 5, respectively, by only the addition of a cysteine residue to the C-terminal end of the peptides. Claims 18 and 20 recite that the plurality of the peptide epitopes, as specified in claims 3 and 14 respectively, is the same one of the peptide epitopes.
Blalock teaches peptide epitopes with 100% sequence identity to instant SEQ ID NOs: 2 and 4, which also have 91% sequence identity to instant SEQ ID NOs: 3 and 5, respectively. Blalock teaches the peptide epitopes coupled to diphtheria toxin as the carrier protein (page 8, lines 25-26; page 6, lines 9-15; claims 4-7; Table 5). Blalock teaches this protein epitope-coupled DT treats MG in humans (page 1, lines 5-9). Blalock teaches this composition comprises a buffer, 25-750 micrograms of the peptide epitopes, and a vaccination adjuvant (claims 8-10; page 6, lines 9-24). Blalock teaches the tryptophan residue at position 8 of SEQ ID NO:2 is or is not alkylated on the free carbon of its indole group (claim 1-2; page 4, line 23 through page 5, line 9). Blalock teaches a plurality of the same one of the peptide epitopes and a combination of different peptide epitopes coupled to the carrier protein (page 7-8). Blalock teaches a method of making the composition by synthesis the peptides and coupling them to the carrier protein (claims 18-22; page 10-11). Alignments between Blalock SEQ ID NOs: 1 and 2 with instant SEQ ID NOs: 3 and 5, respectively, are shown below. Instant SEQ ID NOs: 3 and 5 contain instant SEQ ID NOs: 2 and 4, respectively.
[AltContent: textbox (Alignment between Blalock SEQ ID NO: 1 and instant SEQ ID NO: 3 )]
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[AltContent: textbox (Alignment between Blalock SEQ ID NO: 2 and instant SEQ ID NO: 5 )]
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Blalock does not explicitly teach the mutant Diphtheria Toxin or its sequence corresponding to instant SEQ ID NO: 1. Blalock does not explicitly teach SEQ ID NOs: 3 or 5. Blalock does not explicitly teach a method of making the composition which includes activating the carrier protein with a heterobifunctional crosslinking agent and purifying the composition by removing unreacted substrates and by-products. Blalock does not explicitly teach peptide epitopes coupled covalently to free -NH2 residues of the carrier protein. Blalock does not explicitly teach peptide epitopes coupled to the carrier protein via a heterobifunctional crosslinking agent that is reactive for an amine group and a sulphydryl group.
Arumugham teaches a mutant of the diphtheria toxin carrier protein with 100% sequence identity to instant SEQ ID NO: 1. Arumugham teaches this peptide carrier protein, CRM197, is non-toxic (column 16), creates a more effective immunogenic composition (column 13), and is useful as an immunogen, wherein peptide immunogens are conjugated to protein carriers via activated functional groups on amino acid residues of the carrier (abstract). Arumugham teaches a cysteine residue added the C-terminal of a peptide epitope to facilitate conjugation onto the carrier protein (column 22, lines 21-26; column 5 & 10-14; example 1; claims 1-27; figure 1). Arumugham teaches that one or more peptide epitopes can be coupled covalently to at least 22 free -NH2 residues of the carrier protein (figure 1; example 4-6 & 8; table 8-13). Arumugham teaches the peptide epitopes coupled to the carrier protein with identical sequence to SEQ ID NO: 1 via a heterobifunctional crosslinking agent that is reactive for an amine group and a sulphydryl group (example 1; figure 1; column 5, 21-22, 24-26). Arumugham teaches a method of making the pharmaceutical composition by first activating the carrier protein SEQ ID NO: 1 with a heterobifunctional crosslinking agent, removing any unincorporated crosslinking agent, coupling peptide epitopes to the activated carrier protein, then separating the peptide epitope-coupled carrier protein from any unreacted substrates and by-products, and then dissolving the peptide epitope-coupled carrier protein in an aqueous solution comprising a buffer so as to ensure a specified pH or lyophilizing the peptide epitope-coupled carrier protein (example 2-3; column 28). Alignment between Arumugham SEQ ID NO: 40 and instant SEQ ID NO: 1 is shown below. To summarize, Arumugham teaches all of the limitations required in the instant claims that are not explicitly taught by Blalock.
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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 Blalock and Arumugham. One with ordinary skill in the art would be motivated to make and use the claimed invention because Arumugham teaches a mutant of the diphtheria toxin carrier protein that is both non-toxic and creates a more effective immunogenic composition. An ordinary artisan would find it obvious to substitute the diphtheria toxin carrier protein taught by Blalock for the improved version taught by Arumugham. An ordinary artisan would be motivated to make and use the claimed invention by using Arumugham’s carrier in Blalock’s composition to create a more effective treatment for MG.
Further, Arumugham not only teaches a better version of the carrier protein, but also provides for a method of using the improved carrier protein. In the pursuit of making and using the claimed invention, an ordinary artisan would follow the method taught by Arumugham to utilize the mutant diphtheria toxin carrier protein by adding cysteines to the C-termini of the peptide epitopes to facilitate their conjugation to the carrier protein. An ordinary artisan would find it obvious to follow the method taught by Arumugham for conjugating peptide epitopes to the mutant diphtheria toxin carrier protein, including using a heterobifunctional crosslinking agent that is reactive for an amine group and a sulphydryl group. To make and use the invention, Arumugham further provides a method to synthesize and purify. An ordinary artisan would be motivated to use this method to make and use this product for the treatment of MG. 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.
The prior art only differs from the claimed invention with respect to the claimed amounts and/or ranges of components in the pharmaceutical composition. The Court 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 formulation 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 various ranges of micrograms of SEQ ID NOs: 3 and/or 5 (page 4, lines 14-23; page 8, lines 8-12 & 22-27) and various ranges of the number of free -NH2 residues to which peptide epitopes are coupled covalently (page 3, lines 26 through page 4, lines 1-3), which is evidence of noncriticality to the claimed invention.
Therefore, claims 1-20 are obvious in view of the disclosures of Blalock and Arumugham.
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of co-pending Application No. 18/278,978. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are recited above.
The co-pending claims recite a pharmaceutical composition comprising a conjugated peptide consisting of SEQ ID NO:1 to which a plurality of peptide epitopes have been grafted covalently (claims 1-9, 12-15, & 22), a method for immunization of a patient comprising administering the pharmaceutical composition (claims 10-11), and a method of making the pharmaceutical composition (16-21 & 23-24).
Instant SEQ ID NO: 1 and co-pending SEQ ID NO: 1 have identical sequence. Whereas the instant claims recite specific peptide epitopes attached to the carrier protein, the co-pending claims recite any peptide of at least 7 amino acids attached to the carrier protein. As instant claims 1-7, 10-13, and 18-19 recite the identical carrier protein as co-pending claims 1-9, 12-15, & 22 in a pharmaceutical composition, the more specific and limiting composition of the instant claims are encompassed by the co-pending claims because the co-pending claims encompass any composition containing the carrier protein SEQ ID NO: 1. As instant claims 8-9 recite the identical carrier protein used in a composition to treat MG as co-pending claims 10-11, the more specific and limiting composition used to treat MG of the instant claims are encompassed by the co-pending claims because the co-pending claims encompass any composition containing the carrier protein SEQ ID NO: 1 that’s used to treat MG. As instant claims 14-17 and 20 recite the identical carrier protein as co-pending claims 16-21 & 23-24, the more specific and limiting composition produced by the method of making recited in the instant claims are encompassed by the co-pending claims because the co-pending claims encompass any method of making a composition containing the peptide-attached carrier protein SEQ ID NO: 1. Therefore, claims 1-20 are rejected as being unpatentable over co-pending Application No. 18/278,978. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
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/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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