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 .
Election/Restrictions
Applicant's election with traverse of Group I (i.e., claims 1-14 drawn to a method for obtaining a composition comprising melanin bound to a modified peptide) in the reply filed on September 16, 2025, is acknowledged. Additionally, Applicant's election with traverse of Species A (i.e., L-Dopa as a single and specific melanin precursor and oxygen as a single and specific parameter in which the oxidative polymerization is performed, and a Cysteine at the N-terminus of a peptide as a single and specific modified peptide); Species B (i.e., cancer as a single and specific disease the immunostimulatory composition protects or treats); and Species C (i.e., SEQ ID NO: 29 as a single and specific peptide) in the reply filed on September 16, 2025, is acknowledged.
The traversal is on the grounds that all claims are directed to a single general inventive concept under PCT Rule 13.1, namely, modification at the N-terminus of an immunologically active peptide to enable it to be combined with formed melanin, as an adjuvant, to obtain an immunostimulatory composition (See Applicant’s Response received on 9/16/25, pg. 7). The claims of Groups I and the compositions of Group II explicitly recite this inventive concept, while the peptides of Group III are modified peptides that fall within the same concept (See Applicant’s Response received on 9/16/25, pg. 7). Moreover, contrary to the Examiner’s position that the modified peptide encompasses a vast array of structurally unrelated peptides without a common core structure and/or sequence, Applicant asserts that the claimed peptides are unified by a common structure feature: each bears the addition of a nucleophilic amino acid at the N-terminus (See Applicant’s Response received on 9/16/25, pg. 7).
This is not found persuasive. As indicated in the Restriction mailed on 7/16/25, there is no unifying concept shared among all three Groups. This is because the modified peptide of Groups I and II are not free peptides as the peptides of Group III. Rather, the modified peptide of Groups I and II have a melanin conjugated to it. The peptides of Group III are also specific peptides with defined amino acid sequences whereas the modified peptides of Groups I and II only require a specific residue at the N-terminus of the peptide, and even then, the N-terminal residue is added to the peptide. There is no indication whether a residue is added to the N-terminus of one of the claimed peptides of Group III. Furthermore, even if the N-terminal residue of one of the specific peptide sequences of Group III could be considered one of the added residues, a single residue is insufficient to unite such a large and diverse genus of peptides; peptides with any number of total residues, charge, and/or properties, etc. However, even if a determination that all three Groups share a unifying concept, the concept would be any peptide with one of the 7 residues recited in claim 1 at the N-terminus. As will be discussed below, Carpentier et al. teaches such a peptide, i.e., a peptide modified by the addition of a tail of positively charged amino acids, e.g., lysine. The process of making and/or intended use of the peptide would not be a component of the unifying concept because Group III does not require any limitation other than specific peptide sequences. Thus, contrary to Applicant’s argument the three Groups do not share an unifying concept, and even if they did, the shared technical feature would lack unity of invention in light of the teachings of Carpentier et al.
Additionally, as indicated in the Restriction mailed on 7/16/25, the shared technical feature between Groups I and II is a composition comprising a melanin bound to a modified peptide where the modified peptide comprises one or more nucleophilic residues. The shared technical feature in light of the amended claims remains similar in nature, i.e., an immunostimulatory composition comprising a synthetic melanin bound to a modified peptide where the modified peptide contains one or more epitopes from an antigen and has been modified by the addition of one to six amino acids containing a nucleophilic residue at the N-terminus of the peptide selected from cysteine, acetylcysteine, methionine, proline, hydroxyproline, histidine and lysine, and where the one or more epitopes is able to generate an immune response against such antigen. As discussed in the Restriction, the composition of Group II is prepared by the process of Group I. As such, the composition of Group II encompasses a product-by-process limitation. Regarding product-by-process claims, the Federal Circuit has found that "[e]ven through product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim in the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." See MPEP 2113 and In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Furthermore, the Federal Circuit found that “[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes.” See MPEP 2113 and Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). In the instant case, the product made by the process, i.e., a composition comprising synthetic melanin conjugated to any modified peptide with one of the recited 7 residues at the N-terminus of the peptide, constitutes the required structure of the composition of Group II. The process recited in Group I, i.e., claim 1, does not require any step that imparts a modification to the structure of the product not already present. Notably, performing oxidative polymerization of a melanin precursor, still results in the melanin that is then conjugated to the modified peptide via mixing the two components together under any conditions and/or parameters. As such, the methods steps required by the process of Group I do not impart structure to the composition of Group II. Furthermore, the peptide containing one or more epitopes from an antigen, and able to generate an immune response against the antigen constitute inherent properties of the peptide amino acid sequence and/or intended uses of the modified peptide, respectively. Pursuant to MPEP 2112.01(II), “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. As such, since there is only one residue at the N-terminus of the peptide that is required structurally, any peptide that has one of the added N-terminal residues will necessarily constitute at least one epitope from an antigen and be able to generate an immune response against the antigen.
Furthermore, as discussed in the Restriction, Carpentier et al. teaches melanin conjugated to a modified peptide where the peptide is modified by the addition of a tail of positively charged amino acids, e.g., lysine. Carpentier et al. further teaches a species of modified peptide as SEQ ID NO: 7: VYDFFVWL with adding arginines or lysines to the N-terminus (See Carpentier, Example 14). Notably, SEQ ID NO: 7 contains an epitope derived from Trp2 (See Carpentier, Example 14). Thus, Carpentier et al. teaches conjugating melanin to a modified peptide such as SEQ ID NO: 7 with added arginines or lysines at the N-terminus. Therefore, contrary to Applicant’s argument, the amended shared technical feature between Groups I and II still lacks unity of invention in light of the teachings of Carpentier et al.
The requirement is still deemed proper and is therefore made FINAL.
Regarding Applicant’s election of Species A(3), i.e., a single and specific modified peptide, please note that the Examiner is interpreting Applicant’s election as encompassing any peptide amino acid sequence with an added cysteine residue. Since Applicants elected a broad genus without indicating a specific sequence, Applicant’s election does not per se encompass election of specific species of peptides unless such species were to come up during the Examiner’s search. Thus, as indicated in the “Status of Claims” section, instant claim 7 is withdrawn since Applicants did not elect any of the specific peptide sequences.
Also, please note that in light of the Examiner’s search, Species A regarding the residue to be added to the N-terminus of a peptide is expanded to include lysine.
Status of Claims
Claims 1-22 were originally filed on August 18, 2022.
The amendment received on August 18, 2022, amended claims 1-19. The amendment received on September 16, 2025, canceled claims 3-5; and amended claims 1-2.
Claims 1-2 and 6-22 are currently pending and claims 1-2, 6, 8-10, and 12-14 are under consideration as claims 15-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, and claims 7 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on September 16, 2025.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/053865 filed February 17, 2021, and claims priority under 119(a)-(d) to European Application No. 20305173.5 filed on February 21, 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for European Application No. 20305173.5, which papers have been placed of record in the file. Please note that the European application is in English and therefore no further action is necessary.
Response to Arguments
Applicant’s arguments, see Response, filed 10/22/25, with respect to the specification objection have been fully considered and are persuasive. The objection of the specification has been withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-2, 8-10, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Carpentier et al. WO 2017/089529 A1 published on June 1, 2017 (cited in the IDS received on 8/18/22), alone or as evidenced by, Nosanchuk et al., Antimicrobial Agents Chemother. 50:3519-3528 (2006).
For claims 1-2 and 8-10, with respect to a method for obtaining a composition comprising melanin bound to a modified peptide by (a) providing a synthetic melanin obtained by an oxidative polymerization of a melanin precursor; and (b) mixing the synthetic melanin with a peptide containing one or more epitopes from an antigen, and that is able to generate an immune response against such antigen, wherein the peptide has been modified by addition of one or more amino acids containing a nucleophilic residue to obtain the composition comprising melanin bound to the modified peptide where the amino acid is lysine and wherein the amino acid has been added at the N-terminus of the peptide as recited in instant claim 1; with respect to where the synthetic melanin is in the form of particles of less than 500 nm as recited in instant claim 2; with respect to where the melanin precursor is L-dopa as recited in instant claims 8-9; and with respect to where the oxidative polymerization is performed in presence of oxygen as recited in claim 10:
‘529 teaches immunostimulatory compositions comprising an antigen and a melanin macromolecule that can be used as a vaccine where it is preferred that the antigen and the melanin are complexed to each other (See ‘529, pg. 28, 5th-6th paragraph). The melanin in the composition is obtained after oxidative polymerization of melanin precursors in the presence of the antigen (See ‘529, pg. 29, 3rd, 6th paragraph). It is preferred that the melanin is a soluble melanin that is in the form of particles of small size, i.e., less than 500 nm (See ‘529, pg. 29, 3rd paragraph) thereby satisfying the claim limitation as recited in instant claim 2. A soluble melanin composition can be obtained by filtration of the composition obtained after polymerization with a filter having adapted size of pores (See ‘529, pg. 29, 4th paragraph). The antigen may be present in solution with the melanin precursor or may be bound to the melanin precursor via a covalent bond (See ‘529, pg. 29, last paragraph). This is achieved by linking a melanin precursor to the antigen (See ‘529, pg. 29, last paragraph). When the antigen is a peptide, it is, in particular, possible to bind the melanin precursor to the N- or C-terminal of the peptide (See ‘529, pg. 29, last paragraph to pg. 30, 1st paragraph). It is particularly easy to do so when the melanin precursor is tyrosine or Dopa (See ‘529, pg. 11, 2nd to 3rd paragraph; pg. 30, 1st paragraph) thereby constituting where the melanin precursor is L-dopa as recited in instant claims 8-9. In Example 10, the polymerized L-Dopa (i.e., melanin) is linked to the N- or C-terminus of an ovalbumin epitope depicted as SEQ ID NO: 2 where both conjugates triggered an immune response (See ‘529, pg. 41, 6th paragraph; Example 10). The resulting composition is immunogenic since it is characterized as being a soluble melanin composition from which the antigen is hardly detectable as a free form in solution, and which is able to induce an immune response against the antigen (See ‘529, pg. 30, 2nd paragraph) thereby constituting where ‘529’s antigen is a peptide containing one or more epitopes from an antigen and is able to generate an immune response against such antigen as recited in instant claim 1(b). The mixture of the melanin precursor and the antigen is also exposed to an oxidizing agent in order to promote polymerization to melanin (See ‘529, pg. 30, 6th paragraph). ‘529 teaches that preferred oxidizing agents are chosen from the group consisting of oxygen, hydrogen peroxide, ammonium persulfate and ferric ions (See ‘529, pg. 21, 6th paragraph). As such, the teachings of ‘529 satisfy the claim limitation where the oxidative polymerization is performed in the presence of oxygen as recited in instant claim 10.
In an embodiment, ‘529 teaches a method for obtaining an immunostimulatory composition by (a) providing a composition containing melanin precursors and an antigen, and (b) inducing polymerization of the melanin precursor so as to form a melanin-antigen complex, thereby obtaining an immunostimulatory composition able to elicit an immune response against the antigen when administered to a patient or when incubated with cells in vitro (See ‘529, pg. 33, 2nd paragraph). In Example 1, ‘529 teaches that the ovalalbumin epitope depicted as SEQ ID NO: 2 or the immunogenic human gp100 epitope depicted as SEQ ID NO: 3 is mixed with L-Dopa and incubated for 18 hours in the presence of oxygen to promote oxidation to form immunostimulatory compositions (See ‘529, pg. 37, 1st-2nd paragraph; Example 1). Although the ‘529 steps mix the antigen and melanin precursor and then a synthetic melanin is obtained which is bound to the antigen via oxidative polymerization as opposed to performing oxidative polymerization on a melanin precursor and then mixing the resulting synthetic melanin with the antigen as instantly claimed in claim 1, it is noted that the instant method does not exclude that instants steps (a) and (b) can be performed together. Pursuant to MPEP 2111.01(II), "[t]hough understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment." See Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order). Here, it is noted that the end result in both the ‘529 and instant methods are the same, i.e., a composition comprising synthetic melanin bound to the N-terminus of an antigen peptide via an added nucleophilic residue(s) where the composition is to induce an immune response against the antigen once administered to a host or in vitro to cells. There are no required claimed parameters or conditions, e.g., pH, temperature, concentration, etc., that distinguish the ‘529 steps from the instant steps. Similarly, there is no claim language that requires step (a) to be performed prior to step (b).
Moreover, assuming arguendo, that the claim is amended to require instant steps (a) and (b) to performed in order, in Example 7, ‘529 either mixed the hgp100 antigen peptide with L-Dopa at pH 8.5, incubated the mixture for 18 hours in the presence of oxygen to promote oxidation, or mixed the hgp100 antigen peptide to a solution of L-Dopa that has been previously incubated in the presence of oxygen to promote oxidation before the epitope was added (See ‘529, pg. 39, 6th to 8th paragraph; Example 7). As such, the latter mixing constitutes where synthetic melanin is obtained via oxidative polymerization of a melanin precursor prior to mixing the antigen peptide with the melanin. Although, Figure 6 depicts that a significant CD8 immune response was seem when the epitope was co-incubated with L-Dopa as compared to when the epitope was added after polymerization, as will be discussed below, the epitope was not modified by adding one or more nucleophilic residues to the N-terminus. Thus, the improved CD8 immune response when the antigen is added prior to polymerization does not per se teach away from performing instant steps (a) and (b) of claim 1 in order.
Furthermore, in Example 12, L-Dopa or dopamine solutions were incubated with or without the ovalalbumin epitope at pH 7.4 or 8.5. and with different oxidizing agents (O2 and ammonium persulfate) for 20 hours (See ‘529, pg. 42, 3rd paragraph; Example 12). When the L-Dopa solution was incubated with oxygen at pH 8.5, the Dopa solutions did not precipitate even after centrifugation (See ‘529, pg. 42, 4th paragraph; Example 12). These Dopa solutions remained stable for several weeks and no aggregates were seen with light microscopy (See ‘529, pg. 42, 4th paragraph; Example 12). ‘529 concludes that both compounds can be successfully used in vaccine formulations (See ‘529, pg. 42, 5th paragraph; Example 12). As such, the L-Dopa solutions underwent oxidative polymerization in the presence of O2 prior to mixing with an antigen peptide, and thus, synthetic melanin would necessarily be obtained given that oxidative polymerization is the only instantly claimed required step in claim 1 prior to mixing with the antigen peptide. Thus, the teachings of ‘529 encompass embodiments where synthetic melanin is obtained via oxidative polymerization prior to mixing an antigen peptide to form a complexed/conjugated melanin-antigen composition.
Therefore, the teachings of ‘529 suggest a method for obtaining a composition comprising melanin bound to a peptide by performing instant steps (a) and (b) as recited in instant claim 1.
With respect to adding one or more nucleophilic residue to the N-terminus of the peptide, ‘529 teaches that since melanin precursors are generally charged, e.g., presence of carboxyl groups will provide negative charges such as DHICA (See ‘529, pg. 27, 6th paragraph). However, other precursors such as DHI are neutral or positively charged (See ‘529, pg. 27, 6th paragraph). In order to improve the immunostimulatory property of the composition, it is preferred that the antigen presents a neutral charge or a charge that is opposite to the charge of the melanin (See ‘529, pg. 27, last paragraph). As such, ‘529 teaches that when using Dopa or DHICA as the melanin precursor, it would be advantageous that the antigen is positively charged (See ‘529, pg. 28, 1st paragraph). Importantly, the whole charge of the antigen does not need to be positive, but the antigen shall present at least a region that is positively charged (See ‘529, pg. 28, 1st paragraph). This can be obtained by adding tails of positively charged amino acids to the antigen (See ‘529, pg. 28, 1st paragraph). When dopamine or DHI are used as the melanin precursors, the antigen can have a neutral or negative charge (See ‘529, pg. 28, 2nd paragraph). Adjusting the charge of the antigen improves the formation of the melanin-antigen complex by allowing the antigen and the melanin precursor to be close to each other through charge attraction before oxidative polymerization (See ‘529, pg. 28, 3rd paragraph). Furthermore, ‘529 teaches that the antigen comprises one or several MHC epitopes, or consists of a MHC epitope which is flanked, at its N- and/or C-terminus by a few amino acids (between 1 and 10, preferably between 1 and 6 amino acids at one or both C- and N-terminal ends) (See ‘529, pg. 24, 6th to last paragraph; pg. 25, 1st to 3rd paragraph). In particular, ‘529 further teaches a species of modified peptide as SEQ ID NO: 7: VYDFFVWL with adding arginines or lysines to the N-terminus (See Carpentier, pg. 43, 5th to 6th paragraph; Example 14). Notably, SEQ ID NO: 7 contains an epitope derived from Trp2 (See Carpentier, pg. 43, 5th to 6th paragraph; Example 14). Plus, ‘529 teaches a second species of modified peptide as SEQ ID NO: 8: SFAVATTAL (i.e., a viral epitope of gPr73) with adding a lysine residue at the N-terminus, which significantly enhanced the immune response (See Carpentier, pg. 43, last paragraph; Example 14). As such, ‘529 teaches specific species of modified peptides containing one or more epitopes from an antigen and that has been modified by addition of one or more amino acids containing a nucleophilic residue at the N-terminus of the peptide where the residue is lysine as recited in instant claim 1(b).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to follow the teachings of ‘529 and obtain an immunostimulatory composition comprising soluble melanin bound to a modified peptide by (1) mixing L-Dopa as a melanin precursor, which displays a COO- moiety that is negatively charged, and an antigen peptide such as 529’s SEQ ID NOs: 7 or 8 that has been modified by adding one or more lysine(s) to the N-terminus thereby adding a positive charge to the N-terminus and enhancing the immune response against the antigen peptide, and (2) subjecting the mixture to polymerization conditions such as exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours to induce polymerization of the L-Dopa to soluble melanin while allowing for the formation of an immunostimulatory composition comprising soluble melanin bound to the modified antigen peptide via the positively charged modified N-terminus of the antigen peptide.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because soluble melanin was known to be obtained from L-Dopa via oxidative polymerization in the presence of oxygen as an oxidizing agent at a pH of 8.5 for 20 hours; and because an antigen peptide was known to be modified at the N- and/or C-termini such that the antigen peptide’s charge is opposite that of a melanin precursor’s charge, e.g., SEQ ID NOs: 7 or 8 modified by the addition of a lysine(s) to the N-terminus, which was known to improve the formation of the melanin-antigen complex by allowing the antigen and the melanin precursor to be close to each other through charge attraction before oxidative polymerization and enhance the immune response against the antigen as taught by ‘529.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that an immunostimulatory composition comprising a melanin-antigen complex of ‘529 was obtained by (a) providing a composition containing melanin precursors and an antigen, and (b) inducing polymerization of the melanin precursor so as to form a melanin-antigen complex, thereby obtaining an immunostimulatory composition able to elicit an immune response against the antigen when administered to a patient or when incubated with cells in vitro. Therefore, substituting L-Dopa as the melanin precursor with a negative charge, substituting SEQ ID NOs: 7 or 8 where each antigen peptide is modified by adding one or more lysine(s) to the N-terminus as the antigen thereby resulting in a positively charged N-terminus and enhancing the immune response against the antigen peptide, and utilizing oxidative polymerization in the presence of oxygen at a pH of 8.5 for 20 hours as the polymerization would support the polymerization of the L-Dopa to soluble melanin while allowing for the formation of an immunostimulatory composition comprising soluble melanin bound to the modified antigen peptide via the positively charged modified N-terminus of the antigen peptide by utilizing the KSR rationales: (1) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, and/or (2) simple substitution of one known element for another to obtain predictable results.
For claim 12, with respect to where the synthetic melanin is first purified by filtration on a 10 kDa filter before being mixed with the peptide:
‘529 teaches that it is possible to obtain a soluble melanin composition by filtration of the composition obtained after polymerization with a filter having adapted size of pores (See ‘529, pg. 29, 4th paragraph). Furthermore, as discussed supra for claim 1, although not preferred, ‘529 teaches that the soluble melanin is obtained via oxidized polymerization from a melanin precursor, in particular, L-Dopa, and then the soluble melanin is mixed with an antigen. Since melanin has a negative charge as evidenced by Nosanchuk (See Nosanchuk, pg. 3519, col. 1, 1st paragraph), an ordinary skilled artisan would have a reasonable expectation that this obtained negatively charged melanin would bind with the modified positive charge of the one or more lysine(s) at the N-terminus of an antigen peptide in a similar manner as suggested by ‘529 between L-Dopa and an antigen peptide.
Furthermore, in Example 12, L-Dopa or dopamine solutions were incubated with or without the ovalalbumin epitope at pH 7.4 or 8.5. and with different oxidizing agents (O2 and ammonium persulfate) for 20 hours (See ‘529, pg. 42, 3rd paragraph; Example 12). When the L-Dopa solution was incubated with oxygen at pH 8.5, the Dopa solutions did not precipitate even after centrifugation (See ‘529, pg. 42, 4th paragraph; Example 12). This Dopa solution can be filtered through a 0.2 µm filter but not through a 100 kDa cut off filter (approx. 0.01 µm) (See ‘529, pg. 42, 4th paragraph; Example 12). These Dopa solutions remained stable for several weeks and no aggregates were seen with light microscopy (See ‘529, pg. 42, 4th paragraph; Example 12). Plus, in Example 17, a solution of L-Dopa was mixed with an antigen peptide (i.e., SEQ ID NO: 9) where the mixture was oxidized at pH 8.5 in aerated conditions (See ‘529, pg. 45, 5th paragraph; Example 17). This preparation was then filtered on a 10 kDa filter to demonstrate that the antigen peptide was bound to the melanin (See ‘529, pg. 45, 6th paragraph; Example 17). Although a 10 kDa filter was used to purify the preparation, this filtration step occurred after the melanin was mixed with the peptide.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to follow the teachings of ‘529 and obtain an immunostimulatory composition comprising soluble melanin bound to a modified peptide by (1) obtaining soluble melanin via oxidative polymerization with conditions of exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours from L-Dopa as a melanin precursor, (2) purifying the obtained soluble melanin solution via filtration with a 10 kDa filter, and (3) mixing the filtered soluble melanin solution having a negative charge with a modified antigen peptide an antigen peptide such as 529’s SEQ ID NOs: 7 or 8 that has been modified by adding one or more lysine(s) to the N-terminus thereby adding a positive charge to the N-terminus and enhancing the immune response against the antigen peptide whereby the negatively charged soluble melanin binds to the positively charged N-terminus of the antigen peptide thereby forming a soluble melanin-peptide complex.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because soluble melanin was known to be obtained from L-Dopa via oxidative polymerization in the presence of oxygen as an oxidizing agent at a pH of 8.5 for 20 hours; because an antigen peptide was known to be modified at the N- and/or C-termini such that the antigen peptide’s charge is opposite that of a melanin precursor’s charge, e.g., SEQ ID NOs: 7 or 8 modified by the addition of a lysine(s) to the N-terminus, which was known to improve the formation of the melanin-antigen complex by allowing the antigen and the melanin precursor to be close to each other through charge attraction before oxidative polymerization and enhance the immune response against the antigen; because a soluble melanin composition was known to be obtained by filtration of the composition obtained after polymerization with a filter having adapted size of pores; and because a preparation comprising melanin-antigen complex was known to be purified via filtration with a 10 kDa filter thereby constituting a finite number of solutions to be purified via filtration with a 10 kDa filter, i.e., before inducing complexation of the soluble melanin with the antigen peptide or after the formation of the complex between the soluble melanin with the antigen peptide as taught by ‘529.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that an immunostimulatory composition comprising a melanin-antigen complex of ‘529 was obtained by (1) obtaining soluble melanin via oxidative polymerization with conditions of exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours from L-Dopa as a melanin precursor, (2) purifying a preparation containing the obtained soluble melanin after polymerization but before mixing with the antigen peptide by filtration with a filter having adapted size of pores, and (3) mixing the purified soluble melanin with an antigen peptide. Therefore, substituting SEQ ID NOs: 7 or 8 where each antigen peptide is modified by adding one or more lysine(s) to the N-terminus as the antigen peptide thereby resulting in a positively charged N-terminus and enhancing the immune response against the antigen peptide, and utilizing a 10 kDa filter to filter the obtained soluble melanin preparation given the finite number of solutions to be purified via filtration with a 10 kDa filter would support the formation of an immunostimulatory composition comprising negatively charged soluble melanin bound to the modified antigen peptide via the positively charged modified N-terminus of the antigen peptide by utilizing the KSR rationales: (1) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, and/or (2) simple substitution of one known element for another to obtain predictable results and/or (3) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
For claim 13, with respect to where an immune adjuvant is added to the composition comprising melanin bound to a modified peptide before administration to a host:
‘529 teaches that the immunostimulatory composition can also comprise another immunostimulatory molecule, i.e., an adjuvant (See ‘529, pg. 31, 2nd paragraph). Examples of adjuvants to be include are TLR3 agonists or TLR9 agonists in combination with poly I:C or CpG oligonucleotides (See ‘529, pg. 31, 3rd paragraph). Furthermore, ‘529 defines an adjuvant as a substance that has the capacity to modify or enhance the immune response to an antigen (See ‘529, pg. 22, 6th paragraph). Thus, the added adjuvant taught by ‘529 would necessarily exhibit the functional property of being an immune adjuvant. Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Additionally, ‘529 teaches that the adjuvant can be added with the antigen before initiation of the polymerization of the melanin precursor or after polymerization has occurred (See ‘529, pg. 31, 5th paragraph; pg. 33, 5th). As such, since the adjuvant is added to modify or enhance the immune response to an antigen, and the immunostimulatory composition can be used to generate an immune response against the antigen, it would necessarily follow that the adjuvant is added to the composition, especially when added before polymerization initiation, before administration to a host. Therefore, the teachings of ‘529 satisfy the claim limitation as recited in instant claim 13.
For claim 14, with respect to where the composition is conditioned for administration to a host:
As discussed supra for claim 1, ‘529 teaches, in Example 10, that the polymerized L-Dopa (i.e., melanin) is linked to the N- or C-terminus of an ovalbumin epitope depicted as SEQ ID NO: 2 where both conjugates triggered an immune response (See ‘529, pg. 41, 6th paragraph; Example 10). These conjugates and SEQ ID NO: 2 were administered to mice (See ‘529, pg. 41, 6th paragraph; Example 10). Since these conjugates were administered to a host to evaluate whether an immune response is induced against the epitope, it must follow that the composition comprising each conjugate has been conditioned for administration to the mice. Thus, the teachings of ‘529 satisfy the claim limitation as recited in instant claim 14.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Carpentier et al. WO 2017/089529 A1 published on June 1, 2017 (cited in the IDS received on 8/18/22), alone or as evidenced by, Nosanchuk et al., Antimicrobial Agents Chemother. 50:3519-3528 (2006), as applied to claim 1 above, and further in view of Krieg et al. US Publication No. 2009/0142362 A1 published on June 4, 2009, as applied to claim 6 herewith.
For claim 1, please see discussion of ‘529 supra.
For claim 6, with respect to where a cysteine is added to an N-terminus of the peptide:
As discussed supra for claim 1, ‘529 teaches the antigen peptide can be modified. In particular, ‘529 teaches that the antigen comprises one or several MHC epitopes, or consists of a MHC epitope which is flanked, at its N- and/or C-terminus by a few amino acids (between 1 and 10, preferably between 1 and 6 amino acids at one or both C- and N-terminal ends) (See ‘529, pg. 24, 6th to last paragraph; pg. 25, 1st to 3rd paragraph). When the antigen is a peptide, it is, in particular, possible to bind the melanin precursor to the N- or C-terminal of the peptide (See ‘529, pg. 29, last paragraph to pg. 30, 1st paragraph). It is particularly easy to do so when the melanin precursor is tyrosine or Dopa (See ‘529, pg. 11, 2nd to 3rd paragraph; pg. 30, 1st paragraph). Furthermore, ‘529 teaches that melanins are heterogenous compounds where 4 types of melanins have been described (See ‘529, pg. 4, 2nd paragraph). One of the 4 types of melanins is pheomelanins in which L-Dopa undergoes cysteinylation by conjugation with glutathione or cysteine, leaving to polymers containing benzothiazine and benzothiazole (See ‘529, pg. 4, 2nd paragraph). As such, since the oxidative polymerization step recited in claim 1(a) is not limited, the inclusion of glutathione or cysteine in order to form pheomelanins as the type of soluble melanin is encompassed. However, ‘529 does not teach or suggest that the antigen peptide is flanked by a cysteine residue at the N-terminus, which could then form a disulfide bond with a sulfhydryl group of pheomelanin.
Krieg et al. teaches improved peptide-based vaccine compositions that when administered to an individual, elicit production of antibodies in the individual that recognize endogenous cholesteryl ester transfer protein (CETP) (See Krieg, [0006]). The composition comprises (a) an antigenic hybrid polypeptide comprising a B cell epitope linked to a universal helper T cell epitope portion, and (b) an adjuvant comprising immunostimulatory oligonucleotides (See Krieg, [0007]-[0009]). In some embodiments, the antigenic hybrid polypeptide and adjuvant are linked where the linkage can be direct or indirect (See Krieg, [0017]). Krieg et al. teaches that the two peptide portions of the antigenic hybrid polypeptide can be linked directed via a peptide bond, linked via a linker molecule, which may or may not be a peptide, or linked indirectly to one another by linkage to a common carrier molecule (See Krieg, [0064]). For example, an antigenic hybrid polypeptide can have an amino terminal group that permits the polypeptide to be linked to other molecules, as when the polypeptide has an amino terminal cysteine residue (See Krieg, [0066]). The sulfhydryl group of such an amino terminal cysteine provides a convenient means for linking two antigenic hybrid polypeptides together via a disulfide bond (See Krieg, [0066]). The presence of the sulfhydryl group for disulfide bond formation can also be used to link the antigenic hybrid polypeptide to any other molecule, substrate, or particle that is capable of forming a disulfide bond (See Krieg, [0066]). In this way, another molecule, substrate, or particle that has multiple sulfhydryl groups available for disulfide bond formation may serve as a common carrier molecule to make vaccine compositions containing multiple antigenic hybrid polypeptides (See Krieg, [0066]). Thus, Krieg et al. suggests that the antigenic hybrid polypeptide having an added N-terminal cysteine residue thereby constituting the instant modified peptide of claim 1 can form a disulfide bond with another sulfhydryl group of another molecule, substrate, or particle that can serve as a common carrier molecule.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of ‘529 and obtain an immunostimulatory composition comprising soluble melanin bound to a modified peptide by (1) mixing L-Dopa as a melanin precursor, and an antigen peptide such as 529’s SEQ ID NOs: 7 or 8 that has been modified by adding a cysteine residue to the N-terminus, and (2) subjecting the mixture to polymerization conditions such as exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours to induce polymerization of the L-Dopa to a modified pheomelanin while allowing for the formation of an immunostimulatory composition comprising modified pheomelanin bound to the modified antigen peptide via the sulfhydryl group of the N-terminal cysteine of the antigen peptide.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because pheomelanin was known to be obtained from L-Dopa via cysteinylation by conjugation with glutathione or cysteine, leaving to polymers containing benzothiazine and benzothiazole; and because an antigen peptide was known to be modified at the N- and/or C-termini such that the antigen peptide’s charge is opposite that of a melanin precursor’s charge, e.g., SEQ ID NOs: 7 or 8 modified by the addition of a lysine(s) to the N-terminus, which was known to improve the formation of the melanin-antigen complex by allowing the antigen and the melanin precursor to be close to each other through charge attraction before oxidative polymerization and enhance the immune response against the antigen as taught by ‘529; and because antigenic hybrid polypeptides were known to be modified such that a cysteine residue was added to the N-terminus thereby resulting in a free sulfhydryl group that can form a disulfide bond with another free sulfhydryl group of another molecule, substrate, or particle that can serve as a common carrier molecule as taught by Krieg et al.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that an immunostimulatory composition comprising a melanin-antigen complex of ‘529 was obtained by (a) providing a composition containing melanin precursors and an antigen, and (b) inducing polymerization of the melanin precursor so as to form a melanin-antigen complex, thereby obtaining an immunostimulatory composition able to elicit an immune response against the antigen when administered to a patient or when incubated with cells in vitro. Therefore, substituting L-Dopa as the melanin precursor, substituting SEQ ID NOs: 7 or 8 where each antigen peptide is modified by adding a cysteine to the N-terminus as the antigen thereby resulting in a free sulfhydryl group at the N-terminus, and utilizing oxidative polymerization in the presence of oxygen at a pH of 8.5 for 20 hours as the polymerization would support the polymerization of the L-Dopa to a modified pheomelanin while allowing for the formation of an immunostimulatory composition comprising the modified pheomelanin bound to the modified antigen peptide via formation of a disulfide bond between a free sulfhydryl group of pheomelanin and the free sulfhydryl group at the N-terminus of the antigenic peptide by utilizing the KSR rationales: (1) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, and/or (2) simple substitution of one known element for another to obtain predictable results.
Applicants’ Arguments
Applicants contend that the claimed invention is nonobvious because (1) the applied art teaches away from the claimed approach (See Applicant’s Response received 1/20/26, pg. 7-9); (2) an ordinary skilled artisan would not have had a reasonable expectation of success (See Applicant’s Response received 1/20/26, pg. 7 and 9); (3) there was no rational reason to proceed as claimed at the time the invention (See Applicant’s Response received 1/20/26, pg. 7 and 9-10); (4) Nosanchuk does not cure Carpentier’s deficiencies (See Applicant’s Response received 1/20/26, pg. 7 and 10-11); and (5) the specification reports unexpected results rebutting any indicia of obviousness (See Applicant’s Response received 1/20/26, pg. 7 and 11).
Response to Arguments
Applicant's arguments filed 10/22/25 for claims 1-2, 6, 8-10, and 12-14 have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s argument, i.e., the applied art teaches away from the claimed approach, it is found unpersuasive. 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., steps (a) and (b) must be performed separately and cannot be performed simultaneously) 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). Moreover, pursuant to MPEP 2111.01(II), "[t]hough understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment." See Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).
In the instant case, as stated in the rejection supra, the scope of the two steps in claim 1 do not require that step (b) is performed after the synthetic melanin is completely polymerized. In other words, there is no limitation recited that precludes the mixing of the synthetic melanin with the peptide while the synthetic melanin is simultaneously undergoing oxidative polymerization. In particular, recitation of “the synthetic melanin” in step (b) does refer back to the synthetic melanin that is obtained by an oxidative polymerization method in step (a). However, it does not exclude that the mixing step of (b) cannot also be performed while the synthetic melanin is undergoing oxidative polymerization, i.e., one pot synthesis method. As stated in the rejection supra, there are no required method conditions such as pH, temperature and/or time that would preclude the two steps from being performed simultaneously, e.g., step (a) performed at a pH of 3-5 whereas step (b) is performed at a pH of 7-8. The two pH values are incompatible to be performed simultaneously. It is acknowledged that there are multiple ways to indicate that the order of the steps is required. However, without additional and/or modified claim language, the Examiner maintains that the scope of claim 1 encompasses where steps (a) and (b) can be performed simultaneously.
Furthermore, even if the claimed method was amended to require instant step (a) be performed prior to instant step (b), the teachings of ‘529 do not teach away from practicing the method. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In the instant case, as discussed in the rejection supra, it is acknowledged that ‘529’s Example 7 demonstrates that when the L-Dopa is mixed following oxidative polymerization with a non-modified peptide antigen, little to no immune response was observed as depicted in Figure 6. However, those results were based on a non-modified peptide antigen, i.e., the epitope was not modified by adding one or more nucleophilic residues to the N-terminus. As such, this embodiment is not encompassed by the presently claimed invention, and thus, the reason why the rejection is not one of anticipation, or potentially some form of enablement. Importantly, ‘529 provides a motivation to modify the peptide antigen where such modification improves an immune response. More specifically, as discussed in the rejection supra, ‘529 teaches that mixing a peptide antigen with a neutral charge or a charge that is opposite to the charge of the melanin will improve the immunostimulatory property of the composition. As such, ‘529 teaches that when using Dopa or DHICA as the melanin precursor, it would be advantageous that the antigen is positively charged. One way ‘529 teaches for the antigen to have a positive charged region is to modify the peptide antigen by adding tails of positively charged amino acids to the antigen such as arginines or lysines. Example 14 of ‘529 demonstrates an improved immune response when the peptide antigens are modified, for example, with arginines or lysines, albeit, the conjugates are prepared via the one pot synthesis method. Therefore, since ‘529 teaches that modifying a peptide antigen, for example, adding lysines to a termini, improves the immune response of modified peptide antigen when bound to Dopa or DHICA as the melanin, and fails to demonstrate that such an improved immune response only results when performing a one pot synthesis method, it would then follow that ‘529 does not teach away from performing instant steps (a) and (b) consecutively.
In response to Applicant’s second argument, i.e., an ordinary skilled artisan would not have had a reasonable expectation of success, it is found unpersuasive. Pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). Here, as discussed supra, the scope of the instant method does not require that step (a) is performed prior to step (b). However, assuming arguendo, that the instant step (a) must be performed prior to step (b), when considering the teachings of ‘529 as a whole, ‘529 clearly suggests that modifying a peptide antigen, for example, adding lysine residues, such that the charge of the peptide antigen is opposite that of the melanin will improve an immune response. Pursuant to MPEP 2152.02(b), in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. See Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562, 19 USPQ2d 1111, 1115 (Fed. Cir. 1991). Thus, the fact that ‘529 does not reduce-to-practice where the peptide antigen is modified with a nucleophilic residue, does not per se preclude an ordinary skilled artisan from having a reasonable expectation of success to practice the claimed invention in light of the teachings of ‘529. Therefore, contrary to Applicant’s argument, when considering the teachings of ‘529 as a whole, an ordinary skilled artisan would have the requisite expectation of success to practice the claimed invention.
In response to Applicant’s third argument, i.e., there was no rational reason to proceed as claimed at the time the invention, it is found unpersuasive. It is acknowledged that there is not a specific embodiment that reads on all the instant claim limitations recited in instant claim 1. However, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be disclosed in a single embodiment. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed supra, ‘529 suggests that modifying a peptide antigen with one or more nucleophilic residues such as lysine would improve the immune response of the peptide antigen once bound to melanin. Although, ‘529 demonstrates that a non-modified peptide antigen either did not exhibit an immune response or a very low immune response, there is no indication that a modified peptide antigen would exhibit the same result when using a two-step synthesis method. Thus, the Examiner maintains that an ordinary skilled artisan would have the requisite motivation to modify ‘529’s synthesis method such that a conjugate of melanin and a modified peptide antigen is made, irrespective of whether the instant method is performed via a one-step or two-step method.
In response to Applicant’s fourth argument, i.e., Nosanchuk does not cure Carpentier’s deficiencies, it is found unpersuasive. Since Applicants’ first and second arguments are found unpersuasive, for the reasons set forth supra, it is unnecessary for Nosanchuk to cure the alleged deficiencies of ‘529.
In response to Applicant’s fifth argument, i.e., the specification reports unexpected results rebutting any indicia of obviousness, it is found unpersuasive. Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Here, Applicant asserts that the instant specification shows an effective CD8 response when the peptide is added after melanin formation thereby achieving a result not expected by the teachings of ‘529. However, as discussed supra in response to Applicant’s first argument, ‘529 teaches expressly teaches the method of claim 1 in a single embodiment except where the peptide antigen is modified with one or more nucleophilic residues such as lysine. However, ‘529 expressly suggests that modifying a peptide antigen with one or more nucleophilic residues such as lysine improves the immune response of a melanin-peptide antigen conjugate. The difference between the instant method and ‘529 is that the instant method utilizes a modified peptide antigen (note: as discussed supra, the Examiner maintains that the claimed method does not require two steps). As acknowledged by the instant specification, using a modified peptide antigen and increasing incubation time are two critical factors in obtaining a melanin-peptide antigen conjugate exhibiting an immune response (See instant, pg. 27, 3rd paragraph; pg. 28, last paragraph; pg. 30, 2nd paragraph). Thus, one of the critical factors in achieving an improved immune response, i.e., modifying the peptide antigen, is suggested by ‘529. Therefore, the alleged unexpected results would be expected.
Additionally, even if the claimed invention exhibited unexpected results, the results are not commensurate in scope. Pursuant to MPEP 716.02(d), 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. See MPEP 716.02(d). The Federal Circuit has recognized where Applicants have provided comparative tests with the prior art and the claimed invention. See MPEP 716.02(d).
From an examination of the Specification, it is noted that examples 1-2 examined the amount of binding between the melanin and peptide antigen and example 3 examined the immune response of the peptide alone compared to the melanin-peptide antigen. Example 1 demonstrates that the ‘529 melanin-peptide antigen made in a single step where a non-modified peptide antigen, i.e., SEQ ID NO: 1 or 2, is mixed with L-Dopa in a weight ratio of 1:4 and 1:6, and then incubated for 2 hours at pH 8.5 and 60°C exhibited high melanin binding, i.e., 100% or 93% +/- 12% (See instant, pg. 26, last paragraph; Table 2). When the L-Dopa is polymerized under the same conditions, and then the peptides were added in the same weight ratios the melanin binding remained low, i.e., 23% +/- 8% or 9% +/- 6% (See instant, pg. 26, last paragraph; Table 2). There is no indication for duration of the second step. However, as discussed supra, the peptide is not modified. Since ‘529 expressly suggests modifying the peptide antigen with one or more nucleophilic residues such as lysine, the result is expected instead of unexpected.
The distinction between the ‘529 disclosure and the instant specification appears to be the data provided in Example 2, which examines various condition parameters. Example 2 indicates that melanin binding when performing the two-step synthesis method seems to depend upon specific conditions of the nucleophilic residues, pH, and incubation time. Regarding nucleophilic residues, the specification shows that: (1) no binding was seen when the terminal NH2 was blocked by an acetyl group, (2) nucleophilic proline or hydroxyproline can be added at the N-terminus, (3) lateral chain of some nucleophilic residues such as lysine and cysteine allowed a significant binding even when the N-terminus is blocked, and (4) when adding the modified peptide to L-Dopa that has already been polymerized and incubating the solution for 2 hours at room temperature, some melanin binding is observed, albeit, not to the level seen as the one-pot synthesis method (See instant, pg. 27, 3rd paragraph to last paragraph; Table 2). Furthermore, limited binding of peptides is seen when the incubation time is short, i.e., 10 minutes, whereas binding increases with incubation time, pH or temperature (See instant, pg. 28, last paragraph to pg. 29, 1st paragraph). Temperature data is not shown, but Tables 3 and 4 demonstrate that the peptide antigen binding affinity for melanin increases when the incubation time is 18 hours and the pH is 8.5 (See instant, Table 3). Since the reference, i.e., the ‘529 non-modified peptide antigen, exhibits binding affinity of 28% at an incubation time of 18 hours at a pH of 7.4 and 31% at an incubation time of 18 hours at a pH of 8.5 when using the two-step synthesis method, the increased/improved binding affinity of the modified peptide antigen would need to be statistically significant to the reference. Statistical significance in Tables 3 and 4 have not been indicated. The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practically significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”). Furthermore, the pH appears critical when comparing the 2nd and 3rd columns, e.g., in column 2 = 22% for the modified peptide with a N-terminal proline compared to the reference of 28% in Table 3, and 18 hour incubation time compared to 2 hour incubation time in Table 4. Therefore, when considering the data in the specification, it appears that incubation time and pH are critical in achieving increased melanin binding, presuming that the data is statistically significant. However, the data regarding temperature has not been provided to determine if temperature is also critical. Thus, even if the claimed method exhibits unexpected results, the scope of the claimed method is not commensurate in scope with the results described in the specification.
Accordingly, the rejections of claims 1-2, 6, 8-10, and 12-14 are maintained as Applicants’ arguments are found unpersuasive.
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 1-2, 6, 8-10, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,857,227 B2 in view of Krieg et al. US Publication No. 2009/0142362 A1 published on June 4, 2009.
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(See ‘227 claims 16, 18-19, 21, and 23-27 corresponding to issued claims 1-4 and 6-10). As such, the ‘227 claimed invention reads on the instant method of obtaining a composition comprising melanin bound to a modified peptide except that the peptide is not modified by addition of a nucleophilic residue such as a cysteine at the N-terminus of the peptide. Turning to the specification as a dictionary, ‘227 describes that pheomelanin is one type of melanin and is formed from L-Dopa undergoing cysteinylation by conjugation with glutathione or cysteine, leaving to polymers containing benzothiazine and benzothiazole (See ‘227, col. 3, 3rd paragraph). Furthermore, please see discussion of Krieg et al. supra, which suggests modifying an antigenic polypeptide such that a cysteine residue is added to the N-terminus of the polypeptide so that the polypeptide can form a disulfide bond with another free sulfhydryl group on another molecule. Please also see the motivation to modify the ‘227 claimed invention in light of the suggestion of Krieg. Briefly, an ordinary skilled artisan would be motivated with a reasonable expectation of success to obtain a composition comprising pheomelanin bound to a modified antigen peptide by adding a cysteine residue at the N-terminus of the peptide and allowing the free sulfhydryl group of the cysteine form a disulfide bond with a free sulfhydryl group of pheomelanin via oxidative polymerization of L-Dopa in the presence of oxygen. Additionally, an ordinary skilled artisan would routinely optimize the filter size of a filter in order to purify the melanin. Plus, since ‘227 administers the obtained immunostimulatory composition to a subject, it would necessarily that the composition is conditioned for administration. Thus, the ‘227 claimed invention renders obvious the instantly claimed invention when combined with the teachings of Krieg et al. Therefore, the ‘227 claimed invention is not patentably distinct from the instantly claimed invention.
Applicants’ Arguments
Applicants contend that the rejection should be withdrawn because (1) the pending claims and the ‘227 claims are distinct given that the ‘227 claimed invention is directed to a one-step synthesis method whereas the instant claims are directed to a two-step synthesis method (See Applicants Response received on 1/20/26, pg. 13); and (2) the rejection’s reasoning is ambiguous given that it simultaneously invokes oxidative polymerization of L-Dopa while purporting to justify binding to pheomelanin while failing to properly address the actual order of steps in the instant claims (See Applicants Response received on 1/20/26, pg. 14).
Response to Arguments
Applicant's arguments filed 10/22/25 for claims 1-2, 6, 8-10, and 12-14 have been fully considered but they are not persuasive for the following reasons.
Please note that Applicant’s first argument has been addressed supra. Please see the response to Applicant’s first argument for the 103 rejection. Thus, the response will not reiterated herewith.
In response to Applicant’s second argument, i.e., the rejection’s reasoning is ambiguous given that it simultaneously invokes oxidative polymerization of L-Dopa while purporting to justify binding to pheomelanin while failing to properly address the actual order of steps in the instant claims, it is found unpersuasive. The rejection clearly indicates that the ‘227 claimed invention reads on the instant claimed invention except where the peptide antigen is modified with one or more nucleophilic residues. As discussed supra, the instant claimed method does not exclude the two steps occurring simultaneously. Thus, the question is whether an ordinary skilled artisan would modify the ‘227 peptide with one or more nucleophilic residues. The Examiner maintains that the answer is yes in light of the teachings of Krieg. Since pheomelanin is capable of forming a disulfide bond with a free cysteine side chain as disclosed in the ‘227 specification, a peptide antigen that is modified with a cysteine residue as suggested by Krieg would form a disulfide bond with the melanin as it is undergoing oxidative polymerization. Therefore, contrary to Applicant’s argument, the rationale for the rejection is not ambiguous.
Accordingly, the rejection is maintained as Applicants’ arguments are found unpersuasive.
Conclusion
THIS ACTION IS MADE FINAL. 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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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654