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 .
DETAILED ACTION
Response to Election/Restriction filed on May 13, 2026 is acknowledged. Claims 3, 5, 7-8, 11, 14, 17-18, 20-22, 29, 33, 38, 40, 43, 47-48 were canceled. Claims 1-2, 4, 6, 9-10, 12-13, 15-16, 19, 23-28, 30-32, 34-37, 39, 41-42, 44-46, 49-51 are pending in the instant application.
Election/Restrictions
Applicant elected without traverse EGF-like peptide according to SEQ ID NO:12, the first peptide according to SEQ ID NO:18, the second peptide according to SEQ ID NO:33, and having PGE1 as Boc and PG2 as chlorotrityl.
The restriction is deemed proper and is made FINAL in this office action. Claims 10, 12, 13, 15-16, 19, 23-27, 37.39, 41, 44-46, 49, 51 are withdrawn from consideration as being drawn to a non-elected species.
Claims 1-2, 4, 6, 9, 28, 30-32, 34-36, 50 are examined on the merits of this office action.
Claim Rejections - 35 USC § 112, First Paragraph
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, 4, 6, 9, 28, 30-32, 34-36, 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for preparation of certain disclosed embodiments (EGF SEQ ID NO:1) and TGF-a (SEQ ID NO:51) does not reasonably enable a person of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 is directed to a process for preparing an EGF-like peptide comprising the motif of SEQ ID NO: 49, wherein each X is independently a natural or unnatural amino acid and the peptide contains three intramolecular disulfide bonds. The specification further states that the invention encompasses variants, derivatives, analogues, homologues, fragments, and peptides containing non-naturally occurring amino acid analogues. Variants may contain additions, deletions, substitutions, modifications, replacements, and variations of amino acid residues, including multiple substitutions and non-natural amino acids. Accordingly, the claims encompass an extremely broad genus of EGF-like peptides possessing substantial sequence diversity.
In determining whether the disclosure enables the full scope of the claimed invention, the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), have been considered.
Nature/Breadth of claims
The claimed invention concerns the synthesis of EGF-like peptides containing six cysteine residues and three intramolecular disulfide bonds. Successful preparation of such peptides requires not only peptide assembly but also appropriate folding and disulfide bond formation. Variations in amino acid sequence may affect oxidation behavior, folding pathways, aggregation tendencies, product stability, purification characteristics, and overall recovery of the desired peptide product. Thus, the nature of the invention weighs in favor of a finding that additional experimentation would be required across the full scope of the claims.
Claim 1 encompasses peptides defined by a generalized motif in which each variable position may independently be any natural or unnatural amino acid. The specification further expands the scope of the invention to encompass variants, derivatives, analogues, homologues, fragments, and mimetics. The resulting number of potential peptide sequences encompassed by the claims is extraordinarily large when compared with the limited number of disclosed examples.
State of the Prior Art
The specification acknowledges that peptide synthesis techniques, fragment condensation methods, deprotection strategies, and oxidation procedures were known in the art. The specification further acknowledges difficulties associated with prior syntheses of EGF-family peptides, including low yields, purification difficulties, and challenges associated with obtaining correctly folded products. While the prior art provided general peptide synthesis methodologies, it did not establish that all peptides encompassed by the presently claimed genus could be routinely prepared using the disclosed process.
Predictability or Unpredictability of the Art/The Relative skill in those in the Art
The art is not fully predictable with respect to the synthesis and folding of EGF-like peptides. The specification itself recognizes difficulties associated with preparing EGF-family peptides and emphasizes the need for improved methods. Furthermore, the claimed peptides contain six cysteine residues that must form three intramolecular disulfide bonds. Changes in amino acid sequence, particularly extensive substitutions or incorporation of non-natural amino acids, may affect folding behavior, oxidation pathways, disulfide pairing, solubility, stability, and purification. Consequently, successful preparation of peptides throughout the full scope of the claims is not sufficiently predictable.
A person of ordinary skill in the art possessed significant expertise in peptide synthesis, protection strategies, coupling chemistry, purification techniques, and oxidation chemistry. However, the existence of skilled artisans does not eliminate the need for guidance sufficient to practice the full scope of the claimed invention. Even a highly skilled artisan would be required to engage in substantial experimentation to determine whether the disclosed process successfully prepares the numerous peptide embodiments encompassed by the claims.
Amount of Direction or Guidance Presented
Although the specification provides guidance regarding the preparation of EGF and TGF-α, little guidance is provided regarding peptides containing numerous substitutions, peptides incorporating non-natural amino acids, analogues, mimetics, or substantially modified variants. The specification broadly states that substitutions, additions, deletions, and non-natural amino acids may be employed, but provides little instruction regarding how the disclosed process should be adapted to successfully prepare such embodiments. Consequently, the amount of guidance provided is not commensurate with the breadth of the claimed genus.
Presence or Absence of Working Examples
The specification contains working examples directed to EGF and TGF-α. However, the claims encompass a much broader genus of EGF-like peptides. The specification does not provide working examples demonstrating preparation of analogues, mimetics, peptides containing multiple non-natural amino acids, peptides containing extensive sequence variation from EGF or TGF-α, or other representative members spanning the breadth of the claimed genus. Accordingly, the number of working examples is limited relative to the breadth of the claims.
Quantity of Experimentation Necessary
The quantity of experimentation necessary to practice the full scope of claim 1 would be substantial. The specification provides detailed synthetic examples only for EGF and TGF-α. However, the claims encompass peptides containing extensive amino acid substitutions, insertions, deletions, derivatives, analogues, mimetics, and non-natural amino acids. A person of ordinary skill in the art would be required to determine appropriate fragment boundaries, coupling conditions, deprotection conditions, oxidation conditions, folding conditions, and purification conditions for numerous structurally distinct peptide embodiments encompassed by the claims. Such experimentation would need to be repeated across a vast number of potential peptide sequences falling within the scope of SEQ ID NO: 49.
Conclusion
After consideration of the Wands factors, the specification is not enabling for the full scope of claim 1. Although the disclosure teaches preparation of EGF and TGF-α, it does not provide sufficient guidance, representative examples, or predictive principles enabling one of ordinary skill in the art to make and use the full scope of EGF-like peptides encompassed by claim 1, including peptides containing substantial sequence variation, non-natural amino acids, analogues, derivatives, homologues, fragments, and mimetics, without undue experimentation. Accordingly, claim 1, and claims dependent thereon, are rejected under 35 U.S.C. § 112(a) for lack of enablement.
Claims 1, 2, 4, 6, 9, 28, 30-32, 34-36, 50 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Claims
Independent claim 1 is directed to a process for preparing an “EGF-like peptide” comprising an amino acid sequence having the generic motif: C¹(X)C²(X)4-8C³(X)10-13C⁴(X)C⁵(X)6C⁶ where C¹-C⁶ are cysteine residues, each X is independently a natural or unnatural amino acid, and the peptide contains three intramolecular disulfide bonds. The claim is not limited to epidermal growth factor (EGF) or transforming growth factor alpha (TGF-α). Rather, the claim encompasses any peptide satisfying the recited cysteine-spacing pattern. The specification further states that the invention encompasses variants, derivatives, analogues, homologues, fragments, mimetics, and peptides containing non-naturally occurring amino acid analogues. Claim 50 claims variants of SEQ ID NO:1 (see claim 50, EGF). The claims also claim variants and analogues thereof (claims 6, 28, 30 and 50). Regarding claim 50, “variants” thereof can be any amino acid sequence as there is no core required of claim 50 and no requirement of cysteine residues at all. Thus, the claim encompasses preparing any EGF like peptide (not requiring the structure of the sequences in claim 50) via the process recited in instant claim 50.
Applicants define variants to be any given sequence is a sequence in which the specific sequence of amino acid residues has been notified in such a manner that the peptide in question retains at least one of its endogenous functions (see paragraph 0078). Furthermore, regarding analogue (claim 6), Applicants state “The term “analogue” as used herein in relation to peptides includes any mimetic, that is, a chemical compound that possesses at least one of the endogenous functions of the peptides which it mimics” (see paragraph 0080).
Accordingly, the claim encompasses an extremely broad genus of peptides having substantial sequence diversity.
Actual Reduction to Practice
The specification provides detailed synthetic examples for human EGF (SEQ ID NO: 1) and TGF-α (SEQ ID NO: 51). The disclosure includes protected peptide fragments, fragment coupling strategies, protecting groups, and oxidation/deprotection procedures for these specific peptides. However, the record does not demonstrate reduction to practice of the full genus encompassed by claim 1. The disclosed examples are limited to EGF and TGF-α and do not demonstrate preparation of the vast number of additional peptides encompassed by the generic sequence motif of SEQ ID NO: 49 (which only has cysteines defined), particularly peptides containing substantial sequence variation or non-natural amino acid substitutions that are required to maintain endogenous functions.
Sufficient Relevant Identifying Characteristics
The specification identifies a large list of members of the EGF family, including EGF, HB-EGF, TGF-α, amphiregulin, epiregulin, betacellulin, and neuregulins etc... However, only EGF and TGF-α are described in detail. The generic motif of SEQ ID NO: 49 identifies only six cysteine positions and broad spacing ranges between those cysteines. The remaining positions are defined as any natural or unnatural amino acid. Such a motif does not provide sufficient structural detail to identify the full scope of peptides encompassed by the claim. Numerous peptides could satisfy the claimed cysteine-spacing pattern while differing dramatically in primary sequence, folding behavior, biological activity, receptor binding characteristics, stability, and synthetic accessibility. The specification does not identify structural features beyond the cysteine motif that would permit one of ordinary skill to recognize which members of the claimed genus are possessed by the inventors and would be capable of being synthesized in the manner of the claims including the defined protecting groups and reagents.
Physical and Chemical Properties
The specification does not disclose physical or chemical properties common to the entire claimed genus. Although all claimed peptides are required to contain six cysteines and three intramolecular disulfide bonds, the specification does not establish that peptides satisfying the SEQ ID NO: 49 motif will necessarily adopt the same tertiary structure; exhibit the same folding pathways; form the same disulfide connectivity; possess similar stability profiles; or exhibit comparable characteristics. The claimed genus encompasses peptides containing natural amino acids, non-natural amino acids, substitutions, deletions, insertions, derivatives, and mimetics. The specification provides no evidence that all such peptides will share common physical or chemical properties merely because they satisfy the cysteine-spacing motif.
Functional Characteristics and Correlation Between Structure and Function
The specification defines variants, derivatives, and analogues in functional terms, requiring retention of at least one endogenous function. However, the disclosure does not establish a correlation between the broad structural genus of SEQ ID NO: 49 and the claimed functional properties. The specification demonstrates that EGF and TGF-α possess biological activity. However, the disclosure does not establish that any peptide satisfying the generic motif of SEQ ID NO: 49 will retain EGF-like activity or any endogenous function. Indeed, because the majority of amino acid positions are unrestricted and may be replaced by natural or unnatural amino acids, many sequences encompassed by claim 1 would reasonably be expected to lose activity, proper folding, biological function, or EGF-like characteristics (to be considered an EGF-like peptide). Accordingly, possession of EGF and TGF-α does not demonstrate possession of all peptides encompassed by SEQ ID NO: 49. The specification lacks evidence of a known correlation between the claimed structural motif and the required endogenous function across the full scope of the claimed genus.
Method of Making
The specification provides detailed procedures for synthesizing EGF and TGF-α using protected peptide fragments, fragment coupling, deprotection, and oxidation. While the disclosure may teach how to synthesize the disclosed species, a method of making representative species does not itself establish possession of the entire claimed genus. The fact that one could theoretically apply the disclosed synthetic protocol to other peptides does not demonstrate that the inventors were in possession of all peptides encompassed by the claim. Written description requires possession of the claimed invention itself, not merely possession of a method that could potentially be used to produce undisclosed embodiments. Furthermore, the disclosure does not demonstrate that every peptide satisfying SEQ ID NO: 49 can be successfully synthesized, folded, oxidized, and functionally expressed using the disclosed procedures. The claim assumes that peptides satisfying the cysteine-spacing motif constitute EGF-like peptides. However, the specification does not demonstrate that the recited cysteine spacing alone is sufficient to confer EGF-like structure or function. A peptide could satisfy the motif of SEQ ID NO: 49 while containing extensive non-conservative substitutions; containing multiple non-natural amino acids; lacking residues important for receptor interaction; exhibiting altered folding behavior; failing to form the correct disulfide pattern; or lacking biological activity altogether (which is desired based on the specification, see paragraph 0081). Thus, peptides falling within the literal scope of claim 1 would not necessarily function as EGF-like peptides merely because they satisfy the recited cysteine-spacing motif.
Conclusion
The specification reasonably demonstrates possession of specific EGF-family members such as EGF and TGF-α and provides detailed synthetic methods for those species. However, claim 1 encompasses a substantially broader genus defined primarily by a cysteine-spacing motif and further expanded by variants, derivatives, analogues, homologues, fragments, mimetics, and non-natural amino acid substitutions. The disclosure does not provide a representative number of species commensurate with the breadth of the claimed genus, nor does it identify structural features sufficient to demonstrate possession of all peptides encompassed by SEQ ID NO: 49. Additionally, the specification does not establish a correlation between the claimed structural motif and the asserted functional characteristics across the full scope of the claim. Accordingly, the specification does not reasonably convey to a person of ordinary skill in the art that the inventors were in possession of the full scope of claim 1 as of the filing date.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
09Exwsd[p\2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s)1, 2, 4, 6, 9, 28, 30, 50 are rejected under 35 U.S.C. 103 as being unpatentable over Neya (J. Chem Soc. Perkin Trans. Pages 2187-2198, cited in Applicant’s IDS) in view of Góngora-Benítez (ACS Comb. Sci. 2013, 15, 217−228) and Yang (protein Science, 1994, 3:pages 1267-1275).
Neya teaches the total synthesis of human Epidermal Growth Factor (h-EGF, Urogastrone), which represents the native baseline molecule of the applicant’s target peptide genus. As shown in Figure 1, Neya discloses the complete 53-amino acid h-EGF sequence containing six cysteine residues arranged in the same relative spacing pattern recited by the applicant’s EGF-like peptide formula (SEQ ID NO: 49), namely seven residues between C1 and C2, five residues between C2 and C3, ten residues between C3 and C4, one residue between C4 and C5, and eight residues between C5 and C6 (Fig. 1, p. 2188).
Neya teaches constructing the EGF peptide through a segment condensation methodology in which smaller protected peptide segments are assembled into increasingly larger intermediates. Neya expressly states that “these 10 segments were further coupled to make four larger fragments” and subsequently coupled to generate still larger EGF-derived intermediates (p. 2189, left column, final paragraph). As shown in Scheme 14, Neya prepares Boc-(1-12)-OH (fragment 17), Boc-(13-53)-OBzl (fragment 19), and ultimately Boc-(1-53)-OBzl (fragment 20), demonstrating successful assembly of the full-length protected EGF sequence from large peptide fragments (p. 2191, Scheme 14). Thus, Neya expressly teaches condensation of large EGF-derived peptide fragments corresponding substantially to the same N-terminal and C-terminal partitioning employed by the applicant.
Neya further teaches that larger fragment condensation reactions were successfully carried out using the WSCD-HOBt coupling methodology. Specifically, Neya reports coupling of fragments (17) and (16) to produce fragment (19), followed by coupling of fragments (19) and (18) to produce the full-length protected EGF peptide fragment (20) (p. 2190, right column, final paragraph; p. 2191, Scheme 14). Neya further reports purification, amino acid analysis, and isolated yields for the resulting intermediates and full-length products (pp. 2190-2191; Table, p. 2190).
Neya additionally teaches selective removal of phenacyl (Pac) ester protecting groups while maintaining side-chain protecting groups intact. Neya states that anthranilic acid/pyridine treatment effectively removed the Pac ester group to generate free carboxylic acid fragments suitable for subsequent condensation reactions (p. 2190, right column, middle paragraphs; Schemes 12 and 13, p. 2191).
Neya teaches that the fully protected full-length product was subsequently treated via a two-step deprotection procedure to remove remaining side-chain protections and form the native disulfide-linked EGF structure (p. 2187, Abstract; p. 2188, left column).
While Neya teaches the complete synthetic framework for preparation of full-length EGF peptides and expressly teaches coupling of large EGF fragments corresponding to residues 1-12 and 13-53, Neya utilizes a Boc/Pac protection strategy requiring HF-based deprotection chemistry and does not expressly disclose the applicant’s preferred Fmoc/tBu orthogonal protection system, chlorotrityl-type acid-labile resin cleavage strategy or the specific deprotection as found in IV(a) or IV(b).
However, Góngora-Benítez teaches that protected peptide fragments are valuable building blocks for fragment condensation approaches and are prepared using Fmoc/tBu solid-phase peptide synthesis while maintaining side-chain protecting groups intact after cleavage from the resin. See p. 217, Abstract; p. 218, left column, section “Protected Peptides and Protected Peptide Fragments for Diverse Applications.”
Góngora-Benítez further teaches that fragment condensation strategies assemble protected peptide fragments and that protected peptide acids having a free C-terminus are desirable intermediates for such coupling reactions. See p. 218, right column, discussing protected acyl-donor and acyl-acceptor peptide fragments and fragment coupling in solution; Scheme 1, p. 218.
Góngora-Benítez additionally teaches acid-labile linkers and resins compatible with Fmoc/tBu chemistry, including trityl-based linkers and 2-chlorotrityl chloride (2-CTC) resin. Table 1, p. 219; p. 220, left column. Góngora-Benítez explains that 2-CTC resin permits cleavage under mild acidic conditions to provide protected peptide fragments while retaining side-chain protecting groups and leaving the C-terminus unprotected. P. 220, left column.
It would have been obvious before the effective filing date of the claimed invention to employ the Boc/Fmoc and trityl, chlorotrityl, or t-butyl protecting-group strategies taught by Góngora-Benítez in the peptide fragment synthesis methods of Neya to generate protected peptide fragments suitable for solution-phase fragment coupling while maintaining orthogonal protection.
One of ordinary skill in the art would have been motivated to do so because Góngora-Benítez teaches that such protecting groups facilitate fragment condensation and preserve side-chain protection during peptide assembly.
There would have been a reasonable expectation of success because Boc, Fmoc, trityl, chlorotrityl, and t-butyl protecting groups were well-known, routinely used peptide-synthesis reagents compatible with fragment condensation chemistry and predictably produce protected peptide intermediates suitable for subsequent coupling and deprotection.
Furthermore, regarding IV(a) and IV(b), Yang teaches oxidative folding and disulfide bond formation of synthetic EGF-like peptides following chemical synthesis and deprotection. Specifically, Yang teaches synthesis of an EGF-like domain containing six cysteine residues and three intramolecular disulfide bonds, followed by cleavage and deprotection using trifluoroacetic acid (TFA) and subsequent oxidative formation of the native disulfide-bond architecture. Yang further teaches that dimethyl sulfoxide (DMSO) oxidation was a recognized method for direct oxidation of cysteine-containing peptides and discusses oxidative folding strategies employing DMSO-containing conditions as well as iodine-mediated removal of Acm-protected cysteine residues to form disulfide bonds. (Yang, p. 478, left column; p. 479, left column; Fig. 1; Materials and Methods section). Yang therefore evidences that, at the time of the invention, oxidative folding of EGF-like peptides after deprotection and the use of DMSO- and iodine-based oxidation methodologies for cysteine-containing peptides were well known in the art.
One of ordinary skill in the art would have been motivated to employ the oxidative folding methodologies taught by Yang in the EGF synthesis framework of Neya because both references concern synthetic EGF-like peptides containing multiple cysteine residues and requiring formation of the native disulfide-bond pattern. Substitution of one known oxidation and folding protocol for another represented a routine optimization yielding predictable results in the preparation of correctly folded EGF-like peptides.
Regarding claim 2, Neya in view of Góngora-Benítez teaches the limitation of claim 2. Góngora-Benítez teaches preparing peptide fragments by coupling two or more peptide sub-fragments using solid phase peptide synthesis techniques. Therefore, the combination teaches preparing the first peptide fragment by coupling two or more peptide sub-fragments.
Regarding claim 4, Neya in view of Góngora-Benítez teaches the limitation of claim 4. Góngora-Benítez teaches preparation of peptide fragments through coupling of multiple peptide sub-fragments using solid phase peptide synthesis. Therefore, the combination teaches preparing the second peptide fragment by coupling two or more peptide sub-fragments.
Regarding claim 6, Neya teaches synthesis of epidermal growth factor (EGF). Accordingly, Neya teaches the recited EGF species. To the extent claim 6 encompasses an analogue or variant thereof, the combination teaches preparation of EGF-like peptides and variants using the same peptide synthesis methodologies. Please note that there is no limitations regarding what peptides can be encompassed by “variant thereof” as this encompasses any sort of modification to the sequence. The only requirement is that the EGF like molecule retain the structure of SEQ ID NO:49.
Regarding claim 9, Neya, as modified by the combination set forth above, teaches or renders obvious the limitation of claim 9. Specifically, the first peptide fragment corresponding to the N-terminal portion of the hBD-3 peptide terminates at Gly¹². Accordingly, the C-terminal amino acid of the first peptide fragment is glycine, as required by claim 9. The combination further teaches the limitation of claim 9 because the selected first peptide fragment used in preparing the linear protected EGF-like peptide terminates in glycine. Therefore, the C-terminal amino acid of the first peptide fragment is glycine.
Regarding claim 28, Neya teaches synthesis of the recited EGF sequence through coupling of peptide fragments corresponding to the claimed N-terminal and C-terminal portions of the sequence. Góngora-Benítez teaches the recited protecting group strategies, including Boc/Fmoc N-terminal protection and chlorotrityl or tert-butyl protecting groups. Therefore, the combination teaches the process of claim 28, including variants thereof. Please note that there is no limitations regarding what peptides can be encompassed by “variant thereof” as this encompasses any sort of modification to the sequence. The only requirement is that the EGF like molecule retain the structure of SEQ ID NO:49.
Regarding claim 30, Neya teaches preparation of EGF through coupling of N-terminal and C-terminal peptide fragments. Góngora-Benítez teaches protected peptide fragments comprising conventional side-chain protecting groups and their assembly by fragment condensation. Therefore, the combination teaches the process of claim 30. Furthermore, claim 30 encompasses SEQ ID NO:12, SEQ ID NO:18, and SEQ ID NO:33, or variants thereof, and the combined teachings render obvious preparation of such EGF peptide variants using the same peptide synthesis and fragment-coupling methodologies.
Regarding claim 50, Neya teaches preparation of the recited EGF sequence and fragment coupling thereof. Góngora-Benítez teaches the recited protecting groups and protected peptide fragment synthesis methodologies. Therefore, the combination teaches the process of claim 50. To the extent claim 50 encompasses variants thereof, the combination teaches preparation of such variants using the same peptide synthesis and fragment condensation techniques. Please note that there is no limitations regarding what peptides can be encompassed by “variant thereof” as this encompasses any sort of modification to the sequence. The only requirement is that the EGF like molecule retain the structure of SEQ ID NO:49. Góngora-Benítez teaches protected acyl donor and acyl acceptor peptide fragments for solution phase fragment coupling (see page 218, right column, Scheme 1, page 218). Such acyl donor peptide fragments inherently require an activated C-terminal carboxylic acid functionality for peptide bond formation.
Regarding the limitation of three intramolecular disulfide bonds, Neya teaches synthesis of human EGF, a peptide containing six cysteine residues that form three intramolecular disulfide bonds in the native folded structure (figure 1, abstract). Accordingly, Neya teaches the claimed EGF like peptide having three intramolecular disulfide bonds. Alternatively, Yang teaches oxidative folding of EGF like peptides to obtain the native intramolecular disulfide bond configuration characteristic of EGF family peptides.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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