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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 11, 2026, has been entered.
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. The amendment received on May 11, 2026, amended claim 1.
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 6/11/26, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 1-2, 8-10, and 12-14 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) has been withdrawn. Please note that the rejection has been modified below in light of Applicant’s amendment to claim 1 requiring step (a) to be performed prior to step (b).
Applicant’s arguments, see Response, filed 6/11/26, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 1 and 6 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), and further in view of Krieg et al. US Publication No. 2009/0142362 A1 published on June 4, 2009 has been withdrawn. Please note that Applicant’s argument regarding the structure of pheomelanin not being reactive with a free sulfhydryl group is found persuasive.
Applicant’s arguments, see Response, filed 6/11/26, with respect to the obviousness-type double patenting rejection have been fully considered and are persuasive. The rejection of claims 1-2, 8-10, and 12-14 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 has been withdrawn. Please note that Applicant’s argument regarding the structure of pheomelanin not being reactive with a free sulfhydryl group is found persuasive.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 6, 8-10, and 12-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP §2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Additionally, it is noted that written description is legally distinct from enablement: “Although the two concepts are entwined, they are distinct and each is evaluated under separate legal criteria. The written description requirement, a question of fact, ensures that the inventor conveys to others that he or she had possession of the claimed invention; whereas, the enablement requirement, a question of law, ensures that the inventor conveys to others how to make and use the claimed invention.” See 1242 OG 169 (January 30, 2001) citing University of California v. Eli Lilly & Co.
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
Claim 1 is drawn 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) after the synthetic melanin has been obtained by oxidative polymerization of the melanin precursor, mixing the synthetic melanin with a peptide containing one or more epitopes from an antigen, where 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 selected from cysteine, acetylcysteine, methionine, proline, hydroxyproline, histidine, and lysine and where the amino acid has been added at the N-terminus of the peptide. The melanin bound to the modified peptide must also exhibit the function of an immune response against the antigen the peptide epitope is derived from. As such, the structural scope of claim 1 encompasses where the melanin precursor can be any melanin precursor, the peptidic epitope can be any peptidic epitope, and the method steps can be performed under any conditions. Moreover, the claimed invention and specification fail to identify the level of melanin binding to the modified peptide needed for the melanin-modified peptide fusion to generate an immune response against the antigen the peptide epitope is derived from to suggest that Applicants were in possession of the claimed genus of any level of melanin-modified peptide binding; for example, 1% melanin binding would exhibit the function of an immune response.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Carpentier et al. WO 2017/089529 A1 published on June 1, 2017 (cited in the IDS received on 8/18/22) examined the CD8 immune response of a melanin-peptide (note: hgp100 epitope of sequence, KVPRNQDWL (SEQ ID NO: 3) that is not N-terminally modified with a nucleophilic residue) obtained via two methods (See Carpentier, Example 7). More specifically, one method includes the instantly claimed steps where the melanin is obtained from DOPA via oxidative polymerization prior to mixing with the peptidic epitope, and the second method includes where the melanin precursor was mixed with the peptidic epitope while melanin is obtained via oxidative polymerization (See Carpentier, Example 7). Both methods utilized the same method conditions, i.e., pH at 8.5 and 18 hour incubation period in the presence of oxygen (See Carpentier, Example 7). However, Carpentier et al. demonstrates that only the melanin-peptide fusion obtained via the one step method resulted in the melanin-peptide fusion exhibiting the function of an immune response (See Carpentier, Example 7; Figure 6). Thus, Carpentier et al. suggests that a melanin-peptide fusion obtained via the claimed two step method would not exhibit the function of an immune response.
Furthermore, Carpentier et al. does not exemplify the level at which melanin binds to the hgp100 antigenic peptide when utilizing the two step method in Example 7. However, the specification states that efficient binding of the antigenic peptide to melanin plays a critical role to obtain biological properties (See instant, pg. 27, 2nd paragraph; Example 2). Plus, the instant specification indicates that a good melanin binding of > 50% correlates to a good biological activity (See instant, pg. 31, 5th paragraph). As such, since Carpentier’s hgp100 peptidic antigen did not exhibit an immune response, an ordinary skilled artisan would expect the melanin binding to be less than 50%. However, the instant specification demonstrates the level of melanin binding to the same peptidic antigen (i.e., instant SEQ ID NO: 1 not modified) as a reference to be 89% (See instant, Table 4), two step method performed at the same conditions, i.e., pH of 8.5 and incubation time of 18 hours (See instant, pg. 30, 2nd to 3rd paragraph). As such, given that the instant method conditions are the same and the instant peptidic antigen is the same in instant Table 4 compared to Carpentier’s Example 7, the melanin-hgp100 fusion as the reference in instant Table 4 that resulted in 89% melanin-peptide binding contradicts the data in Carpentier’s Example 7 because 89% melanin binding would be expected to result in a melanin-peptidic antigen exhibiting an immune response.
Although instant Table 4 demonstrates that the modified peptide, i.e., the hgp100 peptidic antigen modified at the N-terminus with proline, hydroxyproline, cysteine and methionine, resulted in 99% to 100% melanin binding to the peptide thereby exhibiting an increased level of binding relative to the reference fusion protein, the combination of the prior art and instant specification do not clearly identify the level of melanin binding needed for the melanin-modified peptide to exhibit the function of an immune response given the discrepancy between the instant data with the prior art data. In light of this data, the remaining data in the instant specification cannot per se correlate to a melanin-modified peptide exhibiting an immune response against the antigen the peptide is derived from except for instant SEQ ID NO: 1 modified at its N-terminus with a cysteine residue (See instant, pg. 31, 5th paragraph). For example, the instant specification teaches in Table 3 that a different peptidic antigen (i.e., SEQ ID NO: 3 = SIYRYYGL) when modified with proline, hydroxyproline, acetyl-lysine, a dipeptide of acetyl-arginine-cysteine, and acetyl-arginine-methionine only binds to melanin at a level of 41%, 74%, 62%, 42%, and 32%, respectively, under the same method conditions (See instant, Table 3). Based on the combined data of the prior art and instant specification, these melanin-modified peptide fusions would not exhibit an immune response since the level of melanin binding is less than the reference fusion protein in Table 4, and only two specific fusions exhibit a melanin binding greater than 50%. Furthermore, it is noted that the instant specification does not determine or evaluate whether the melanin-modified peptide fusions in Tables 3-4 exhibit an immune response except for a single species of melanin-modified peptide fusion. More specifically, SEQ ID NO: 1 modified by cysteine, which exhibited a melanin binding level of 99%, also exhibited an immune response as depicted in Figure 2 (See instant, pg. 31, 5th paragraph).
Moreover, the instant specification demonstrates in Example 3 three specific species of melanin-modified peptide fusions that exhibit an immune response but not melanin binding level of three additional peptidic antigens, i.e., SEQ ID NOs: 29, 31, and 34 (See instant, Table 5). When each peptidic antigen is modified at the N-terminus with cysteine and bound to melanin (amount of binding not provided), the immune response increased relative to the unmodified and unbound peptidic antigen (See instant, Table 5). Since there is no definitive correlation between the level of melanin binding needed for a melanin-modified peptide to exhibit an immune response and/or a lack of a representative number of species that an ordinary skilled artisan can extrapolate the positive data from in order to extend to the scope of the claimed genus, the instant specification only exemplifies a limited number of peptidic antigens, i.e., SEQ ID NOs: 17, 29, 31, and 34, modified with a limited number of nucleophilic amino acids, i.e., cysteine, that would exhibit the function of immune response generation.
Thus, the disclosure does not allow one of skill in the art to visualize or recognize the level of melanin binding to the modified peptide required to practice the claimed method such that the obtained melanin-modified peptide fusion exhibits an immune response. Accordingly, one of ordinary skill in the art would conclude that the applicant would not have been in possession of the claimed method for obtaining a melanin-modified peptide fusion where this fusion would exhibit an immune response because the level of melanin binding to the modified peptide that is required to practice the method is not adequately described and was not known in the art.
Claims 1-2, 6, 8-10, and 12-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP §2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Additionally, it is noted that written description is legally distinct from enablement: “Although the two concepts are entwined, they are distinct and each is evaluated under separate legal criteria. The written description requirement, a question of fact, ensures that the inventor conveys to others that he or she had possession of the claimed invention; whereas, the enablement requirement, a question of law, ensures that the inventor conveys to others how to make and use the claimed invention.” See 1242 OG 169 (January 30, 2001) citing University of California v. Eli Lilly & Co.
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
Claim 1 is drawn 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) after the synthetic melanin has been obtained by oxidative polymerization of the melanin precursor, mixing the synthetic melanin with a peptide containing one or more epitopes from an antigen, where 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 selected from cysteine, acetylcysteine, methionine, proline, hydroxyproline, histidine, and lysine and where the amino acid has been added at the N-terminus of the peptide. The melanin bound to the modified peptide must also exhibit the function of an immune response against the antigen the peptide epitope is derived from. As such, the structural scope of claim 1 encompasses where the melanin precursor can be any melanin precursor, the peptidic epitope can be any peptidic epitope, and the method steps can be performed under any conditions. However, as will be further articulated below, the prior art and the instant specification demonstrate that (1) specific method conditions for instant step (b) and (2) a specific structural correlation between the obtained synthetic melanin and the modified peptide are necessary for obtaining a melanin-modified peptide fusion via the claimed two-step process.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Carpentier et al. WO 2017/089529 A1 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). 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). However, ‘529 teaches that binding melanin to a peptidic antigen is dependent upon the charge of each component. When utilizing the melanin precursors DHICA, the presence of carboxyl groups will provide negative charges (See ‘529, pg. 27, 6th paragraph). But 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). 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). Thus, ‘529 demonstrates that the formation of a melanin-modified peptide fusion is dependent on the specific peptidic antigen amino acid sequence and charge relative to the melanin precursor charge where modifying the peptidic antigen termini in order to adjust the peptidic antigen charge so that it will bind to the melanin with an opposite charge.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches obtaining specific melanin-modified peptide fusions under specific process conditions. The specification states that efficient binding of the antigenic peptide to melanin plays a critical role to obtain biological properties (See instant, pg. 27, 2nd paragraph; Example 2). In Example 2, melanin binding was examined with the peptide of SEQ ID NO: 3 (i.e., SIYRYYGL) with various N-terminal modifications via two step process, i.e., the instant two step process where the modified peptidic antigen is mixed with a synthetic melanin after the synthetic melanin is obtained via oxidative polymerization, or via a one step process where the two steps are performed simultaneously (See instant, Table 2). The mixing step is performed for 2 hours at room temperature where the weight ratio of peptide to L-Dopa is 1:4 (See instant, pg. 27, last paragraph; pg. 28, 1st paragraph). As depicted in Table 2, the reference peptidic antigen of SEQ ID NO: 3 did not result in any melanin binding when performing the two step process, but when the N-terminus is modified with proline, hydroxyproline or acetyl-arginine-cysteine, the level of melanin-modified peptide binding is 7%, 23%, and 53%, respectively (See instant, Table 2). It is noted that the acetyl-arginine-histidine modified peptide was not examined (See instant, Table 2). It is further noted that the level of melanin binding to this specific peptide epitope after 2 hours of incubation at room temperature is relatively low with only one of the modified peptides being greater than 50%. It is not readily apparent, as stated in the 112(a) rejection supra, that these melanin-modified SEQ ID NO: 3 fusions generate an immune response.
Moreover, the instant specification indicates that incubation conditions were evaluated where limited melanin binding to peptides is seen when the incubation time is short (as disclosed in the Carpentier reference discussed supra) (See instant, pg. 28, last paragraph; Table 3). However, the instant specification demonstrates that increased incubation time, increased pH or increased temperature resulted in improved melanin-modified peptide binding (See instant, pg. 28, last paragraph to pg. 29, 1st paragraph; Table 3). But it is noted that the instant specification does not discuss or show the data related to temperature. As such, it is not readily apparent whether temperature is a critical parameter in obtaining higher melanin-modified peptide binding. Moreover, the instant specification only utilized lysine, cysteine, proline and hydroxyproline as nucleophilic amino acids (See instant, pg. 29, 1st paragraph). As depicted in Table 3, the unmodified peptidic antigen still bound to melanin at 18 hour incubation period and at a pH of 8.5, i.e., 31% (See instant, Table 3). When modifying SEQ ID NO: 3 with proline, hydroxyproline, acetyl-lysine, acetyl-arginine-cysteine, and acetyl-arginine-methionine, the melanin binding after 18 hour incubation period at a pH of 8.5 improved to 41%, 74%, 62%, 42%, and 32%, respectively (See instant, Table 3). In fact, when the nucleophilic residue is acetyl-lysine or acetyl-arginine methionine, there is no melanin-peptide binding observed after 2 hour incubation period at a pH of 7.4. As such, at a minimum, incubation time and pH as method parameters affect the level of melanin to peptide binding (note: a determination of temperature cannot be made), along with the specific nucleophilic residue, e.g., acetyl-arginine-methionine compared to hydroxyproline. Plus, there is no indication whether the melanin-modified peptide fusions depicted in Table 3 exhibited an immune response.
Furthermore, the instant specification examined a second peptidic antigen, i.e., SEQ ID NO: 1 of KVPRNQDWL, which resulted in significantly higher melanin-peptide binding relative to SEQ ID NO: 3 (See instant, Table 4). The instant specification teaches that when melanin is synthesized before the peptide are added, i.e., instant two step process, the melanin binding is enhanced (1) by increasing the incubation time, and (2) when the peptide is modified at the N-terminus with lysine, cysteine, hydroxyproline, or methionine (See instant, pg. 30, 2nd paragraph). Notably, unmodified SEQ ID NO: 1 resulted in a melanin binding level of 89% when incubated for 18 hours (See instant, Table 4). However, it is noted that the pH and temperature at which the incubation time was performed at is not indicated. Distinguishable from the melanin binding level for SEQ ID NO: 3, when SEQ ID NO: 1 is modified with proline, hydroxyproline, cysteine, or methionine at the N-terminus, the melanin binding level for SEQ ID NO: 1 is 100%, 100%, 99%, and 100%, respectively (See instant, Table 4). Plus, the instant specification indicates that a good melanin binding of > 50% correlates to a good biological activity (See instant, pg. 31, 5th paragraph). In particular, SEQ ID NO: 1 modified by cysteine, which exhibited a melanin binding level of 99%, also exhibited an immune response as depicted in Figure 2 (See instant, pg. 31, 5th paragraph). As such, at a minimum, incubation time as a method parameter affects the level of melanin to peptide binding (note: a determination of pH and temperature cannot be made), along with the specific nucleophilic residues, e.g., proline, hydroxyproline, cysteine, or methionine, and specific peptidic antigen sequence, i.e., SEQ ID NO: 1 vs SEQ ID NO: 3. Given the vast difference of melanin binding level between SEQ ID NO: 1 and 3 where only the hydroxyproline and acetyl-lysine modified SEQ ID NO: 1 peptides exhibit a melanin binding level greater than 50% thereby suggestive of biological activity and given the limited process conditions demonstrating a melanin binding level greater than 50%, the specific species in the specification do not constitute a representative number of species that an ordinary skilled artisan can extrapolate the positive data to extend to the full scope of the claimed genus. Thus, the disclosure does not allow one of skill in the art to visualize or recognize the process conditions, i.e., incubation duration, pH and/or temperature, and peptidic antigen sequence including the nucleophilic residue(s) required to practice the claimed method in order to obtain a melanin-modified peptide fusion that exhibits an immune response. Accordingly, one of ordinary skill in the art would conclude that the applicant would not have been in possession of the claimed method for obtaining a melanin-modified peptide fusion because specific process conditions and peptidic antigen structure that is required to practice the method is not adequately described and was not known in the art.
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) after the synthetic melanin has been obtained by oxidative polymerization of the melanin precursor, 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.
Moreover, 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. Furthermore, there are no required claimed parameters or conditions, e.g., pH, temperature, concentration, level of melanin binding, etc., that distinguish the ‘529 steps from the instant steps, other than modifying the peptide with a nucleophilic residue. 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). Therefore, ‘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). Furthermore, 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.
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 a soluble melanin bound to a modified peptide by (1) subjecting L-Dopa as a melanin precursor to polymerization conditions such as exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours to obtain soluble melanin, and then (2) mixing the obtained synthetic soluble melanin 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 thereby allowing for the formation of a soluble melanin bound to the modified antigen peptide via the positively charged modified N-terminus of the antigen peptide where the melanin-modified antigen peptide fusion generates an immune response. 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 prior to mixing with an antigen peptide; 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 soluble synthetic melanin’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 positively charged antigen peptide and the negatively charged soluble melanin to be close to each other through charge attraction 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 ‘529 utilized a two-step process to form a melanin-peptide complex by (a) subjecting L-Dopa as a melanin precursor to polymerization conditions such as exposure to an oxidizing agent such as oxygen at a pH of 8.5 for 20 hours to obtain soluble melanin, and then (2) mixing the obtained synthetic soluble melanin with an antigen peptide where such complex exhibited little to no immune response. Therefore, modifying the antigen peptide such that it has a positive charge by fusing one or more lysine residues at the N-terminus of the antigen peptide thereby allowing the positively charged antigen peptide and the negatively charged soluble melanin to be close to each other through charge attraction would support the formation of a melanin-modified antigen peptide fusion via the two step process and support the melanin-modified antigen peptide fusion exhibiting an enhanced immune response against the antigen 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.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 6/11/26 for claims 1-2, 8-10, and 12-14 have been fully considered but they are not persuasive for the following reasons.
As an initial matter, it is useful to note that the scope of the claimed method encompasses (1) any level of melanin binding, even 1%, when obtaining a melanin-modified peptide fusion from performing the claimed two steps, (2) any process conditions for the second step, i.e., any temperature, pH and/or incubation period, (3) any level of immune response, even 1%, and (4) any antigen peptide.
In response to Applicant’s first and third arguments, i.e., (1) the applied art teaches away, and would not have been modified to arrive at the claimed invention (See Applicant’s Response received on 6/11/26, pg. 8-9), and (3) the claimed method makes operative a post-polymerization approach the prior art showed to be ineffective (See Applicant’s Response received on 6/11/26, pg. 10-11), they are found unpersuasive. 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 stated in the Action mailed on 3/16/26, it is acknowledged that ‘529’s Example 7 demonstrates that when the L-Dopa (i.e., is mixed following oxidative polymerization with a non-modified peptide antigen, little to no immune response was observed as depicted in Figure 6. Although such a result would generally be considered a failed approach, there are two critical considerations that suggest otherwise. First, pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). The Examiner acknowledges that Carpentier’s goal/purpose is to obtain immunostimulatory melanin-antigen compositions capable of inducing an antigen-specific immune response. However, contrary to Applicant’s assertion that the Examiner is conflating two mechanistically distinct teachings in Carpentier, when considering the teachings of Carpentier as a whole there is a direct correlation between the two teachings where an ordinary skilled artisan would expect a different end result if the antigen peptide is modified with one or more lysine residues at its termini. As discussed in the rejection supra, this is because Carpentier expressly 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. 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. However, the process examined in Carpentier’s Example 7 does NOT modify the antigen peptide, and Carpentier does not examine the immune response when modifying the antigen peptide and mixing the synthetic melanin, i.e., already subjected to oxidative polymerization. As such, 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. Pursuant to MPEP § 2144, a difference in objectives, if any, does not defeat the case for obviousness because the “reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) …; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) …” Thus, even though Carpentier modified the antigen peptide termini so that the melanin precursor would favorably bind to the modified antigen peptide during oxidative polymerization, the Examiner maintains that an ordinary skilled artisan would be motivated with a reasonable expectation of success, when considering Carpentier’s teachings as a whole, to modify the antigen peptide so that, when mixed, it would favorably bind with the negatively charged soluble synthetic melanin obtained via oxidative polymerization whereby such modification would also improve the antigen peptide’s immune response against the antigen. Therefore, contrary to Applicant’s argument, the Examiner has not conflated two distinct teachings in Carpentier.
The second consideration is with respect to the level of melanin binding to the antigen peptide in Carpentier’s Example 7. As discussed in the first 112(a) rejection supra, the instantly claimed invention encompasses any level of binding and any amount of immune response. Given that the immune response of the melanin-antigen peptide produced via the two step process in Carpentier’s Example 7 was little to no response, it would be expected that the melanin binding level is also little to none. Notably, Carpentier does not determine or identify the level of melanin binding to the antigen peptide. However, the instant specification performed the same process in Carpentier’s Example 7 and determined the level of melanin binding to the same antigen peptide. More specifically, the instant specification demonstrates the level of melanin binding to the same peptidic antigen (i.e., instant SEQ ID NO: 1 not modified) as a reference to be 89% (See instant, Table 4) where the mixing step was performed at the same conditions as in Carpentier, i.e., pH of 8.5 and incubation time of 18 hours (See instant, pg. 30, 2nd to 3rd paragraph). As such, with such a high level of melanin binding, it would be expected that the melanin-antigen peptide obtained via the two step process would exhibit an immune response. Thus, there is a contradiction between what is expected in Carpentier’s Example 7 and what is demonstrated instant Table 4 such that the PTO is not equipped to conduct experimentation in order to determine the level of melanin binding in Carpentier’s Example 7. Therefore, contrary to Applicant’s arguments, interpreting Carpentier’s Example 7 as a black/white example without considering Carpentier’s teachings as a whole, is misplaced. Accordingly, the Examiner maintains that Carpentier’s teachings do not teach away from arriving at the claimed invention
In response to Applicant’s second argument, i.e., the art shows an expectation of failure, not success (See Applicant’s Response received on 6/11/26, pg. 9-10), 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). In the instant case, as discussed supra, when considering the teachings of ‘529 as a whole, ‘529 clearly suggests that modifying a peptide antigen, for example, adding lysine residues to an antigen termini, 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 and mixed with an already polymerized synthetic melanin, 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.
Regarding Applicant’s statement that Nosanchuk supports a lack of success, it is noted Nosanchuk does not make a general statement that melanin would impair bounded molecules biological activity. Although Nosanchuk teaches that when mixing tobramycin (i.e., an antibiotic) with melanin, there was an immediate decrease in antibiotic activity (See Nosanchuk, pg. 3523, col. 2, 3rd paragraph), Nosanchuk also teaches that there is no difference in activity against melanized and nonmelanized C. neoformans cells for other antibiotics such as fluconazole (See Nosanchuk, pg. 3524, col 1, 2nd paragraph), and that the antipsychotic drug trifluoperazine has a greater fungicidal activity against melanized cryptococcal cells than it did against nonmelanized cells (See Nosanchuk, pg. 3524, col. 2, 1st paragraph). Generally speaking, Nosanchuk et al. examined the effect of antibiotics on microbial cells that contain melanin on/in their cell surface, and does not teach or suggest effects of melanin on an antigen peptide’s immune response. As such, given that (1) Carpentier expressly suggests that a modified antigen peptide rendering it positively charged would enhance the immune response against the antigen when bound to a negatively charged melanin precursor, and (2) that an absolute expectation of success is unnecessary to establish a prima facie case of obviousness, the Examiner maintains that an ordinary skilled artisan would have the requisite expectation of success to modify Carpentier’s teachings as indicated supra to arrive at the claimed invention. 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 fourth argument, the Examiner’s position that Applicant’s evidence is not commensurate in scope with the claims is misplaced (See Applicant’s Response received on 6/11/26, pg. 11-12), it is found unpersuasive. First, Applicant asserts that a prima facie of obviousness is needed before secondary considerations are necessary, which Applicant argues has not been made for the reasons addressed supra (See Applicant’s Response received on 6/11/26, pg. 11). In response – as discussed supra, the Examiner maintains that a prima facie case of obviousness has been made.
Second and third, Applicant asserts that (2) secondary considerations need only address some portion of the claimed scope, which was done in the instant application such that adding an N-terminally modified peptide to already formed melanin would restore binding and immune activity in the post-polymerization process, and (3) objective evidence need not test or prove every embodiment within the literal scope of a claim (See Applicant’s Response received on 6/11/26, pg. 11-12). In response – as stated in the Action mailed on 3/16/26, 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). As discussed supra, Carpentier suggests modifying a termini of an antigen peptide in order to ensure the antigen peptide exhibits a positive charge that will bind to a negatively charged melanin where such modification results in an improved immune response. The difference between the instant method and ‘529 is that the instant method utilizes a modified peptide antigen. Since Carpentier suggests Applicant’s proposed unexpected results, the results would expected, not unexpected.
Furthermore, even if the claimed invention exhibits unexpected results, the scope of the claimed invention is not commensurate in scope with the evidence provided in the specification. As discussed supra, the scope of the claimed method encompasses a number of parameters that are not limited. The instant specification supports that additional factors are required in order to restore binding and immune activity in the post-polymerization process. More specifically, the instant specification teaches that efficient binding of the antigenic peptide to melanin plays a critical role to obtain biological properties (See instant, pg. 27, 2nd paragraph; Example 2). Plus, the instant specification indicates that a good melanin binding of > 50% correlates to a good biological activity (See instant, pg. 31, 5th paragraph). Notably, the claimed invention does not limit the level of melanin binding to the antigen peptide. Plus, the instant specification indicates that incubation conditions were evaluated where limited melanin binding to peptides is seen when the incubation time is short (as disclosed in the Carpentier reference discussed supra) (See instant, pg. 28, last paragraph; Table 3). However, the instant specification demonstrates that increased incubation time, increased pH or increased temperature resulted in improved melanin-modified peptide binding (See instant, pg. 28, last paragraph to pg. 29, 1st paragraph; Table 3). But it is noted that the instant specification does not discuss or show the data related to temperature. As such, a determination of whether temperature is a critical parameter in obtaining higher melanin-modified peptide binding cannot be made. Moreover, the instant specification only utilized lysine, cysteine, proline and hydroxyproline as nucleophilic amino acids (See instant, pg. 29, 1st paragraph). When modifying SEQ ID NO: 3 with proline, hydroxyproline, acetyl-lysine, acetyl-arginine-cysteine, and acetyl-arginine-methionine, the melanin binding after 18 hour incubation period at a pH of 8.5 improved to 41%, 74%, 62%, 42%, and 32%, respectively (See instant, Table 3). In fact, when the nucleophilic residue is acetyl-lysine or acetyl-arginine methionine, there is no melanin-peptide binding observed after 2 hour incubation period at a pH of 7.4. As such, at a minimum, incubation time and pH as method parameters affect the level of melanin to peptide binding (note: a determination of temperature cannot be made), along with the specific nucleophilic residue, e.g., acetyl-arginine-methionine compared to hydroxyproline. Plus, there is no indication whether the melanin-modified peptide fusions depicted in Table 3 exhibited an immune response.
Furthermore, the instant specification examined a second peptidic antigen, i.e., SEQ ID NO: 1 of KVPRNQDWL, which resulted in significantly higher melanin-peptide binding relative to SEQ ID NO: 3 (See instant, Table 4). The instant specification teaches that when melanin is synthesized before the peptide are added, i.e., instant two step process, the melanin binding is enhanced (1) by increasing the incubation time, and (2) when the peptide is modified at the N-terminus with lysine, cysteine, hydroxyproline, or methionine (See instant, pg. 30, 2nd paragraph). Notably, unmodified SEQ ID NO: 1 resulted in a melanin binding level of 89% when incubated for 18 hours (See instant, Table 4). However, it is noted that the pH and temperature at which the incubation time was performed at is not indicated. Distinguishable from the melanin binding level for SEQ ID NO: 3, when SEQ ID NO: 1 is modified with proline, hydroxyproline, cysteine, or methionine at the N-terminus, the melanin binding level for SEQ ID NO: 1 is 100%, 100%, 99%, and 100%, respectively (See instant, Table 4). As such, at a minimum, incubation time as a method parameter affects the level of melanin to peptide binding (note: a determination of pH and temperature cannot be made), along with the specific nucleophilic residues, e.g., proline, hydroxyproline, cysteine, or methionine, and specific peptidic antigen sequence, i.e., SEQ ID NO: 1 vs SEQ ID NO: 3. Thus, although it is acknowledged that not every embodiment claimed must be tested or proved to exhibit the alleged unexpected result, since there is vast difference of melanin binding level between SEQ ID NO: 1 and 3 where only the hydroxyproline and acetyl-lysine modified SEQ ID NO: 1 peptides exhibit a melanin binding level greater than 50% thereby suggestive of biological activity, given the limited process conditions demonstrating a melanin binding level greater than 50%, and given the broad scope of the claimed invention, the specific species in the specification do not constitute a representative number of species that an ordinary skilled artisan can extrapolate the positive data to extend to the full scope of the claimed genus. For these reasons, the evidence provided in the instant specification cannot support the broad scope of the claimed invention; in other words, the evidence provided in the instant specification is not commensurate in scope with the claimed invention.
Accordingly, the rejection of claims 1-2, 8-10, and 12-14 is maintained as Applicants’ arguments are found unpersuasive.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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