DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on April 17, 2026, is acknowledged. The traversal is on the ground(s) that the N-acetyl group in the compound taught by PINTO does not impart enhanced stability and CNS penetration provided by the claimed compounds. This is not found persuasive. First, in response to applicant's argument that PINTO fails to show certain features, it is noted that the features upon which applicant relies (i.e., antinociceptive activity coupled with enhanced stability and CNS penetration) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Second, the species taught by PINTO, which is characterized by having acetyl at variable R, is specifically included in the genus not only in Formula I in claim 1 but as specifically recited in dependent claim 8. Finally, as shown in the anticipation rejections below, numerous species of Formula I are known in the prior art. The requirement is still deemed proper and is therefore made FINAL.
Claims 16-17 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Nucleotide and/or Amino Acid Sequence Disclosures
The amendment filed July 23, 2026, to address sequence compliance is acknowledged. However, there are additional issues in the application.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located at Figures 1, 2, and 4, and in paragraphs [0004], [0008], [0021], [0052], [0079], and [0080].
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Drawings
The drawings are objected to because the figure legends for Figures 5A and 5B are inconsistent with the labels in the figures. The figure legends for Figures 5A and 5B refer to human cerebrospinal fluid and mouse plasma, respectively, whereas the labels in Figures 5A and 5B state mouse plasma and human cerebrospinal fluid, respectively. Applicant should amend the figure legend or drawing. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 requires that R is (CF3)2-CHOH-CO, HO-CHCH2OH-CO, (CH3)2-COH-CO, NH2-CH-(CH3)2-CO, (CH3)3-CH2CO, or (CH3)2- CHOH-CH2-. However, these alternatives violate the chemical rule that carbon forms four bonds. For example, in (CF3)2-CHOH-CO the bolded C is bonded to CF3, CF3, H, OH and CO, which is five bonds. In HO-CHCH2OH-CO the bolded C is bonded to OH, H, CH2, OH and CO, which is five bonds. In (CH3)2-COH-CO the bolded C is bonded to CH3, CH3, OH, and CO, which is five bonds. In NH2-CH-(CH3)2-CO the bolded Cs are bonded to three H atoms, a C atom, and either CH or CO, which is five bonds. In (CH3)3-CH2CO, two of the methyl group carbons is bonded to three H atoms and two carbon atoms, which is five bonds. In (CH3)2-CHOH-CH2- one of the methyl group carbons is bonded to three H atoms and two carbon atoms, which is five bonds.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 8, 12, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pinto et al. (Modification with Organometallic Compounds Improves Crossing of the Blood-Brain Barrier of [Leu³]-Enkephalin Derivatives in an In Vitro Model System. ChemBioChem 2009, 10, 1852-1860; hereafter “PINTO”).
Claim interpretation: the claim term “acyl” includes C(O)CH3 in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be alkyl.
PINTO teaches (Figure 2)
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wherein
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which is a species of instant Formula (I) wherein R is an acyl, Y is CH2CH(CH3)2, and X is OH. PINTO teaches that all amino acids are enantiomerically pure L amino acids (p. 1857, col. 1, para. 2).
Because a species anticipates a genus, claim 1 is anticipated by PINTO.
Regarding claim 2, the claim defines the nature of the optional substitution but does not require that the R group is substituted. Therefore, compound 2 taught by PINTO also anticipates claim 2.
Regarding claim 3, R is an acyl in compound 2 of PINTO. Therefore, compound 2 taught by PINTO also anticipates claim 3.
Regarding claim 4, R is an alkanoyl in compound 2 of PINTO. Therefore, compound 2 taught by PINTO also anticipates claim 4.
Regarding claim 8, R is
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in compound 2 of PINTO. Therefore, compound 2 taught by PINTO also anticipates claim 8.
Regarding claim 12, X is OH in compound 2 of PINTO. Therefore, compound 2 taught by PINTO also anticipates claim 12.
Regarding claim 15, PINTO teaches administration of compound 2 in a Krebs-Ringer buffer to PBCECs from pig brain (p. 1858, col. 2, para. 1). The composition comprising compound 2 in Krebs-Ringer buffer is a pharmaceutical composition. Therefore, PINTO anticipates claim 15.
In response to applicant's argument in the response filed April 17, 2026, that PINTO fails to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., antinociceptive activity coupled with enhanced stability and CNS penetration) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claims 1, 3, 12, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zimmer (US 2004/0186058 A1; hereafter “ZIMMER”).
Claim interpretation: the claim term “acyl” includes cinnamoyl (C6H5-CH=CH-C(O)) in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be alkenyl, which may be substituted. The definition of substitutions in specification paragraph [0072] states without limitation and therefore includes C6H5-.
ZIMMER teaches cinnamoyl-YGGFM (Example 1), which is a species of instant Formula (I) wherein R is an acyl, Y is CH2CH2SCH3, and X is OH. ZIMMER teaches YGGFM is a naturally occurring peptide. As a result, the cinnamoyl-YGGFM taught by ZIMMER includes amino acids that are enantiomerically pure L amino acids ([0030]).
Because a species anticipates a genus, claim 1 is anticipated by ZIMMER.
Regarding claim 3, R is an acyl in cinnamoyl-YGGFM of ZIMMER. Therefore, cinnamoyl-YGGFM of ZIMMER also anticipates claim 3.
Regarding claim 12, X is OH in cinnamoyl-YGGFM of ZIMMER. Therefore, cinnamoyl-YGGFM of ZIMMER also anticipates claim 12.
Regarding claim 15, ZIMMER teaches a pharmaceutical composition comprising cinnamoyl-YGGFM in saline for intravenous administration ([0034]). Therefore, ZIMMER anticipates claim 15.
Claims 1, 3, 12, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mou et al. (CN 106083996 A, English translation provided by PE2E SEARCH; hereafter “MOU”).
Claim interpretation: the claim term “acyl” includes gallic acyl (3,4,5-trihydroxybenzoyl C6H2(OH)3-C(O)) in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be aryl, which may be substituted. The definition of substitutions in specification paragraph [0072] includes hydroxyl.
MOU teaches gallic acyl-YGGFM (p. 11 of English translation), which is a species of instant Formula (I) wherein R is an acyl, Y is CH2CH2SCH3, and X is OH. MOU teaches that the peptides contain enantiomerically pure L amino acids.
Because a species anticipates a genus, claim 1 is anticipated by MOU.
Regarding claim 3, R is an acyl in gallic acyl-YGGFM of MOU. Therefore, gallic acyl-YGGFM of MOU also anticipates claim 3.
Regarding claim 12, X is OH in gallic acyl-YGGFM of MOU. Therefore, gallic acyl-YGGFM of MOU also anticipates claim 12.
Regarding claim 15, MOU teaches a dermatological composition comprising gallic acyl-YGGFM (p. 11 of English translation). Therefore, MOU anticipates claim 15.
Claims 1-4, 8, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cogan (WO 2016/157177 A1; hereafter “COGAN”).
Claim interpretation: the claim term “acyl” includes hexanoyl (-C(O)(CH2)4CH3 in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be alkyl.
COGAN teaches N-hexanoyl-leu-enkephalin (Example 7), which is a species of instant Formula (I) wherein R is an acyl, Y is CH2CH(CH3)2, and X is OH. Because a species anticipates a genus, claim 1 is anticipated by COGAN.
Regarding claim 2, the claim defines the nature of the optional substitution but does not require that the R group is substituted. Therefore, N-hexanoyl-leu-enkephalin (Example 7) taught by COGAN also anticipates claim 2.
Regarding claim 3, R is an acyl in N-hexanoyl-leu-enkephalin (Example 7) of COGAN. Therefore, compound 2 taught by PINTO also anticipates claim 3.
Regarding claim 4, R is an alkanoyl in N-hexanoyl-leu-enkephalin (Example 7) of COGAN. Therefore, N-hexanoyl-leu-enkephalin (Example 7) of COGAN also anticipates claim 4.
Regarding claim 8, R is hexanoyl (-C(O)(CH2)4CH3 in N-hexanoyl-leu-enkephalin (Example 7) of COGAN. Therefore, N-hexanoyl-leu-enkephalin (Example 7) of COGAN also anticipates claim 8.
Regarding claim 12, X is OH in N-hexanoyl-leu-enkephalin (Example 7) of COGAN. Therefore, N-hexanoyl-leu-enkephalin (Example 7) of COGAN also anticipates claim 12.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by López-Fandiño et al. (Protease-catalyzed synthesis of oligopeptides in heterogenous substrate mixtures. Biotechnol Bioeng. 1994 May;43(11):1024-30; hereafter “LÓPEZ-FANDIÑO”).
Claim interpretation: the claim term “acyl” includes C(O)CH3 and C(O)CF3 in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be alkyl, which may be substituted. The definition of substitutions in specification paragraph [0072] includes halide.
LÓPEZ-FANDIÑO teach N-Ac-L-[Leu5]-enkephalin amide (10) and N-TFAc-L-[Leu5]-enkephalin amide (11), which are species of instant Formula (I) wherein R is an acyl, Y is CH2CH(CH3)2, and X is NH2. Because a species anticipates a genus, claim 1 is anticipated by LÓPEZ-FANDIÑO.
Regarding claim 2, N-TFAc-L-[Leu5]-enkephalin amide (11) includes an acyl substituted with a halo. Therefore, compound 11 of LÓPEZ-FANDIÑO anticipates claim 2.
Regarding claim 3, R is an acyl in compounds 10 and 11 of LÓPEZ-FANDIÑO. Therefore, compounds 10 and 11 of LÓPEZ-FANDIÑO also anticipate claim 3.
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.
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.
Claims 1-6, 8-12, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer (US 2004/0186058 A1; hereafter “ZIMMER”).
Claim interpretation: the claim term “acyl” includes pivaloyl (-C(O)C(CH3)3) in view of the definition in specification paragraph [0063], which states that acyl is C(O)R1 wherein R1 may be alkyl.
ZIMMER teaches the genus:
Carrier-Linkerx-Peptide
wherein
X is 0 or 1;
Carrier is selected from benzoyl, phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxy-cinnamoyl, 3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl, benzoyloxycarbonyl, pivaloyl, N9-fluorenyl methoxycarbonyl, fumaroyl and derivatives thereof ([0011]); and
Peptide is Tyr-Gly-Gly-Phe-Met ([0014]; Example 1).
ZIMMER reduce to practice the species cinnamoyl-YGGFM (Example 1), which is a species of instant Formula (I) wherein R is an acyl, Y is CH2CH2SCH3, and X is OH. See anticipation rejection above.
ZIMMER do not reduce to practice species wherein Carrier is the other alternatives recited in the genus, including pivaloyl.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make other species in the genus taught by ZIMMER, including pivaloyl-YGGFM. The rationale for obviousness is "obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success (MPEP § 2143.01(E)). The relevant findings for this rationale are as follows.
(1) At the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem. In the instant case, ZIMMER teaches that there is a need to improve the bioavailability of therapeutic peptides such as Met-enkephalin ([0002]-[0014]). Therefore, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem.
(2) There had been a finite number of identified, predictable potential solutions to the recognized need or problem. ZIMMER teach modifying the N-terminal amino group of the peptide with one of fourteen carrier groups to improve its bioavailability ([0002]-[0014]). The number of carrier groups taught by ZIMMER is comparable to the number the courts held as a finite in Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) (the court rejected the notion that unpredictability could be equated with nonobviousness here, because there were only a finite number (53) of pharmaceutically acceptable salts to be tested for improved properties). Therefore, there had been a finite number of identified, predictable potential solutions to the recognized need or problem.
(3) One of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success. One of ordinary skill in the art would expect that the bioavailability of Met-enkephalin would be improved by modifying the N-terminal amino group with pivaloyl because ZIMMER demonstrates that adding a carrier group permits the effective oral absorption of peptides of at least five amino acids in length and allows a much stronger pharmacological effect, with significantly enhanced pharmacokinetic profiles, by both oral and i.v. routes of administration ([0040]). Therefore, one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification does not include evidence of unexpected results for the species pivaloyl-YGGFM.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
The compound pivaloyl-YGGFM is a species of instant Formula I wherein R is an acyl, Y is CH2CH(CH3)2, and X is OH. Therefore, claim 1 is obvious over ZIMMER.
Regarding claim 2, the claim defines the nature of the optional substitution but does not require that the R group is substituted.
Regarding claim 3, R is an acyl in pivaloyl-YGGFM, which is obvious over ZIMMER.
Regarding claim 4, R is an alkanoyl in pivaloyl-YGGFM, which is obvious over ZIMMER.
Regarding claims 5 and 8-11, R is pivaloyl in pivaloyl-YGGFM, which is obvious over ZIMMER.
Regarding claim 12, X is OH in pivaloyl-YGGFM, which is obvious over ZIMMER.
Regarding claim 15, ZIMMER teaches a pharmaceutical composition comprising the modified peptides ([0011], [0022]-[0027]).
Regarding claim 18, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the pharmaceutical compositions comprising the modified peptides with written instructions for the compositions use in treating pain. One of ordinary skill in the art would have been motivated to do so given that ZIMMER teach that the composition is intended for pharmaceutical use and it is standard in the art to provide written instructions with drugs for clinical use. Furthermore, ZIMMER teaches that the modified peptides are effective for pain (Example 1).
Regarding claim 6, ZIMMER teaches that the Carrier may also be derivatives of the groups benzoyl, phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxy-cinnamoyl, 3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl, benzoyloxycarbonyl, pivaloyl, N9-fluorenyl methoxycarbonyl, and fumaroyl. POSITA would envisage -hydroxy and methoxy substitution as a derivative of the carrier groups given that several of the options listed include hydroxy and methoxy substitution of a base structure (e.g. cinnamoyl, 3-OH-cinnamoyl, and 3,4-OH-cinnamoyl; cinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxy-cinnamoyl, and 3,4,5-trimethoxycinnamoyl. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use hydroxy and methoxy substituted derivatives of the carrier groups, which would include claimed options phenylacetyl, dihydroxyl phenylacetyl, trihydroxyl phenylacetyl, dimethoxy phenylacetyl, and trimethoxy phenylacetyl,
Claims 1-6, 8-15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer (US 2004/0186058 A1; hereafter “ZIMMER”), as applied to claims 1-6, 8-12, 15, and 18 above, in further view of Fredholt et al. (Chemical and enzymatic stability as well as transport properties of a Leu-enkephalin analogue and ester prodrugs thereof. Journal of Controlled Release 63 (2000) 261–273; hereafter “FREDHOLT”); and Peppin et al. (Delta opioid agonists: a concise update on potential therapeutic applications. Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 155–166; hereafter “PEPPIN”.
ZIMMER does not teach that the peptide is Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu).
PEPPIN teaches that Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) is highly selective for the delta opoiod receptor (DOR) but that low systemic availability limits clinical utility in applications such as treatment of pain and depression (pp. 159-160, bridging para, part 1).
FREDHOLT teaches that ester prodrugs of the N-terminal tyrosine Leu-enkephalin show improved permeation across biological membranes. The extent of permeation increased with increasing hydrophobicity of the groups acetyl-, propionyl- and pivaloyl (Section 3.4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a carrier-YGGFM, including pivaloyl-YGGFM, for the reasons presented above. It would have been further obvious to apply the same modification strategy taught in ZIMMER for Leu-enkephalin taught by PEPPIN and FREDHOLT to make carrier-YGGFL, including pivaloyl-YGGFL. The rationale for obviousness is 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 (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. In the instant case, the prior art, as represented by PEPPIN and FREDHOLT, teaches that Leu-enkephalin has therapeutic potential for treatment of pain and depression because of its delta-opioid receptor activity (FREDHOLT, section 1; PEPPIN, pp. 159-160, bridging para, part 1). In addition, the prior art teaches that clinical use of Leu-enkephalin is limited by its poor bioavailability (FREDHOLT, section 1; PEPPIN, pp. 159-160, bridging para, part 1). One of ordinary skill in the art would have been motivated to improve the bioavailability of Leu-enkephalin using the strategy taught by ZIMMER, which includes the modification of the N-terminal amino group of a peptide with a carrier group such as a pivaloyl group ([0010]-[0029]). Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success. One of ordinary skill in the art would predict that modification of the N-terminal amino group of Leu-enkephalin with a pivaloyl group would improve bioavailability based on ZIMMER and FREDHOLT. First, ZIMMER demonstrates that N-terminal amino group modification of related peptide Met-enkephalin with a carrier group moiety, of which pivaloyl is an option, is successful (Example 1). Furthermore, FREDHOLT demonstrate that N-terminal modification of the tyrosine hydroxy group in a Leu-enkephalin derivative with pivaloyl was successful (Section 3.4). Therefore, there was a reasonable expectation of success.
(3) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The evidence in the specification regarding KK-103 is insufficient to overcome the prima facie case of obviousness because 1) the results are not commensurate with the full scope of the claims, and 2) the results are expected in view of the cited art.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The compound pivaloyl-YGGFL is a species of instant Formula I wherein R is an acyl, Y is CH2CH(CH3)2, and X is OH. Therefore, claim 1 is obvious over the cited art.
Regarding claim 2, the claim defines the nature of the optional substitution but does not require that the R group is substituted.
Regarding claim 3, R is an acyl in pivaloyl-YGGFL.
Regarding claim 4, R is an alkanoyl in pivaloyl-YGGFL.
Regarding claims 5 and 8-11, R is pivaloyl in pivaloyl-YGGFL.
Regarding claim 12, X is OH in pivaloyl-YGGFL.
Regarding claims 13-14, R is pivaloyl, X is OH, and Y is CH2CH(CH3)2 in pivaloyl-YGGFL.
Regarding claim 6, ZIMMER teaches that the Carrier may also be derivatives of the groups benzoyl, phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxy-cinnamoyl, 3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl, benzoyloxycarbonyl, pivaloyl, N9-fluorenyl methoxycarbonyl, and fumaroyl. POSITA would envisage -hydroxy and methoxy substitution as a derivative of the carrier groups given that several of the options listed include hydroxy and methoxy substitution of a base structure (e.g. cinnamoyl, 3-OH-cinnamoyl, and 3,4-OH-cinnamoyl; cinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxy-cinnamoyl, and 3,4,5-trimethoxycinnamoyl. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use hydroxy and methoxy substituted derivatives of the carrier groups, which would include claimed options phenylacetyl, dihydroxyl phenylacetyl, trihydroxyl phenylacetyl, dimethoxy phenylacetyl, and trimethoxy phenylacetyl,
Regarding claim 15, ZIMMER teaches a pharmaceutical composition comprising the modified peptides ([0011], [0022]-[0027]).
Regarding claim 18, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the pharmaceutical compositions comprising the modified peptides with written instructions for the compositions use in treating pain. One of ordinary skill in the art would have been motivated to do so given that ZIMMER teach that the composition is intended for pharmaceutical use and it is standard in the art to provide written instructions with drugs for clinical use. Furthermore, ZIMMER teaches that the modified peptides are effective for pain (Example 1).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 8:30 am - 5 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRISTINA M MARCHETTI BRADLEY
Primary Examiner
Art Unit 1654
/CHRISTINA M MARCHETTI BRADLEY/Primary Examiner, Art Unit 1654
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