DETAILED ACTION
Examiner acknowledges receipt of the reply and Borchard Declaration filed 1/23/2026, in response to the non-final office action mailed 9/24/2025.
Claims 1, 15-17, 19, 20, and 25-29 are pending. Claims 19, 20, and 25-29 remain withdrawn from further prosecution for the reasons made of record.
Claims 1 and 15-17 are being examined on the merits in this office 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 .
Examiner Comment
After extensive prosecution in this case, it appears that applicants disagree with the examiner's findings and that the disagreement is based on a point of law. In light of this, applicants are reminded of their right to appeal the examiner's rejections to the Board of Appeals and Interferences.
Declaration under 37 CFR 1.132
The Borchard Declaration under 37 CFR 1.132 filed 1/23/2026 is insufficient to overcome the rejection of claims 1 and 15-17 based upon 35 USC 103 and double patenting as set forth in the non-final office action mailed 9/24/2025. Please see the Response to Arguments section below the respective rejections.
Response to Arguments
Applicant's arguments and the Declaration filed 1/23/2026 have been fully considered but they are not persuasive with respect to the following rejections. An action on the merits is set forth herein.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
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 for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 15-17 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Conde et al (WO 93/20101- previously cited), and further in view of Martinez-Rodriguez et al. (Chem Biodivers 7(6):1531-1548 (2010) - previously cited). The rejection is maintained from the office action mailed 9/24/2025.
Conde et al teach peptides of formula (I) and pharmaceutically acceptable derivatives thereof, which peptides contain 3 to 15 amino acid residues and inhibit protein kinase C zeta. The peptides have use in medicine for the treatment of conditions whose underlying etiology is associated with ζ-PKC activity, for example tumors, hyperproliferative disorders and viral infections (abstract). Specific peptides include SEQ ID NOs:3-5. Conde et al. show a preferred inhibitor peptide as Ala-Arg-Arg-Trp-Arg (SEQ ID NO 3) (Example 3; claim 4) with homology to the peptide of instant SEQ ID NO: 4 (ARRWR – all D-amino acids). Conde et al. teach an inhibitor peptide is further modified by myristoylation at the N-terminal amine group (p3, line 13-14), reading on (myristoylation)-ARRWR of the (p. 5,ll. 18-25 of instant specification). The peptides can further comprise D- amino acids (p. 4, ll. 11-14).
Although Conde et al. taught a peptide Myr-ARRWR (SEQ ID NO:3) that can further include D-amino acids, the reference does not explicitly teach that all of the amino acids are D-amino acids [to give SEQ ID NO:4].
Martinez-Rodriguez et al. is a review article discussing the advantages of including D-amino acids in a peptide sequence. The reference teaches that D-amino acid-containing peptides have increased resistance to proteolytic cleavage and are therefore more stable (pp. 1535-1540).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a peptide of Myr-ARRWR, as taught by Conde et al, comprising all D-amino acids in view of the teachings of Martinez-Rodriguez et al. The skilled artisan would have been motivated to do so because Conde et al. taught specific peptides of Myr-ARRWR. The skilled artisan would have had a reasonable expectation of success because Martinez-Rodriguez et al. specifically taught including D-amino acids in a peptide sequence increased peptide stability.
The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969). 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 teachings of Conde et al. and Martinez-Rodriguez et al..
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. In this case, peptide of Myr-ARRWR was known in the art at the time of the invention (see Conde et al.). It was further known in the prior art that D-amino acids stabilized a peptide, as taught by Martinez-Rodriguez et al. The motivation to include all D-amino acids in peptides of Conde et al. to arrive at instant peptide SEQ ID NO:4 can be found in the common knowledge of the art and common sense of its skilled practitioners.
As noted above, Conde et al. taught Myr-ARRWR (SEQ ID NO:3) and can further include D-amino acids, the reference does not explicitly teach that all of the amino acids are D-amino acids. However, this difference is obvious according to the rationale in MPEP § 2143.01(E): "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success. At the time of the invention, there was a recognized problem or need in the art. Specifically, peptides comprising L-amino acids were subject to proteolytic cleavage and therefore less stable therapeutics. To overcome this problem, Martinez-Rodriguez et al. teaches modification of peptides via incorporation of D-amino acids.
At the time of the invention, there had been a finite number of identified, predictable potential solutions to the design of a peptide taught by Conde et al. Conde et al. taught peptide Myr-ARRWR (SEQ ID NO:3). This peptide has 5 amino acids. Thus, there are a finite number of amino acids to incorporate D-amino acids.
In view of these findings, it would have been obvious to prepare a peptide of Myr-AKRWR (SEQ ID) consisting of all D-amino acids. The resulting peptide of SEQ ID NO:4 would satisfy all of the limitations of claim 1. 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.
It would have been obvious to include the D-amino acids taught by Martinez-Rodriguez et al in the peptide of Conde et al in order to improve the stability of the peptide and increase proteolytic resistance. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Accordingly, claims 1 and 13 are rendered obvious in view of the teachings of the cited prior art.
Regarding claims 15 and 16, Conde et al. teach pharmaceutical compositions comprising a peptide and a pharmaceutically acceptable carrier (p. 8, l. 29-p. 10, l. 35; claims 11-14). The pharmaceutical compositions can be the form of oral, nasal compositions. Id. Regarding claim 17, Conde et al teach that the pharmaceutical compositions/ formulations can include other therapeutic or prophylactic agents (p. 8, ll. 32-35; p. 11, l. 20-p.12, l. 8; claims 11-14).
Accordingly, claims 1 and 15-17 are obvious in view of the teachings of Conde et al and Martinez-Rodriguez et al.
Response to Arguments
Applicant traverses the rejection at pp. 2-6 of the reply filed 1/23/2026. Applicant asserts at p. 2:
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Applicant states Martinez-Rodriguez is a review article summarizing examples in which selected L-amino acids are substituted with D- amino acids at specific positions to improve proteolytic stability. Applicant asserts the reference does not teach or suggest full stereochemical inversion of any peptide (reply at p. 2). Applicant asserts the “sole example” of a short all D- amino acid peptides is described in Dooley et al (Ref 112). Applicant asserts the reference does not provide evidence of increased stability relative to a L-peptide. Applicant asserts that Dooley et al does not teach or suggest converting a known L-peptide into an all D-form, nor provide motivation to do so for reversible cell penetrating purposes (reply at p. 3). Applicant asserts neither Martinez-Rodriguez nor any reference cited therein provides a teaching, suggestion, or motivation to perform complete stereoinversion of the peptides disclosed by Conde. Id.
Applicant alleges that the “nature of the problem itself appears to have not been considered in the assessment of motivation” (reply at p. 4). Applicant states that “the problem solved by the peptides the present claims is fundamentally different than those presented in Martinez-Rodriguez”, namely that the cited reference “addresses peptides for which prolonged activity is desired, and partial incorporation of D- amino acids in those context serves to extend activity”. Id. Applicant asserts that the instant claims relate to a reversible activity, specifically reversible tight junction opening is, which leads to a reversible cell permeabilization. Id. Applicant further asserts that increased stability reduces reversibility, and reduces reversibility increases toxicity, citing Holm et al (Biochimica et BIophysica Acta 1808:1544-1551 (2011)). Applicant asserts that Martinez-Rodriguez teaches away from modifications requiring reversible activity (reply at p. 4).
Applicant asserts that the Examiner’s own references “confirm that the outcome of full stereoinversion is unpredictable”- referring to art cited but NOT relied upon- Milton et al and Fitzgerald et al (reply at p. 4).
Applicant asserts that “neither Conde nor Martinez-Rodriguez, alone or in combination, provides a teaching, suggestion, or motivation, nor a reasonable expectation of success, for converting Conde’s all L-peptide into its all-D counterpart” (reply at p. 5).
Applicant asserts that examiner did not respond to arguments relating to potential toxicity that could result from prolonged stability (section 1.4 of replies filed 7/25/2025 and 1/23/2026). Applicant asserts that “examiner may argue that such concerns would not deter the skilled artisan because reasonable expectation of success already exists” (reply at p. 5). Applicant asserts that “no reasonable expectation of success can be found in any of the cited references and combinations thereof. Thus, potential toxicity resulting from increased stability/reduced reversibility would discourage the skilled artisan from attempting complete stereoinversion of the peptide taught by Conde”. Id.
Applicant states at p. 5:
As established above, stereochemical inversion lacks reasonable expectation of success due to absence of teachings regarding (1) maintained or improved reversibility, (2) increased risk of toxicity through increased stability, and (3) unpredictable outcomes due to enantiomer-specific peptide/substrate interaction. Thus, full stereochemical inversion is not a predictable or obvious option.
Applicant asserts that there are other peptides-engineering strategies available to the skilled artisan to improve reversible permeability without increasing toxicity, e.g., PEGylation, peptide stapling, etc. Id. Applicant provides references in IDS and the declaration confirming the scientific accuracy and routine nature of these alternatives. Applicant alleges that even if stereochemical inversion were considered, and represents only one of many design options, without any reasonable expectation of success (reply at pp. 5-6).
Applicant asserts that “Examiner’s position appears to be contradictory: the claimed transient/reversible tight junction feature is alleged to be both not recited in the claims and inherent in the prior art. However, for the reasons stated above, none of the cited prior art provides any reasonable expectation of success to convert an all L-peptide into its all-D counterpart” (reply at p. 6).
Applicant concludes by stating that “the present claims are non-obvious over the combination of Conde and Martinez-Rodriguez” (p. 6).
Borchard Declaration
The declaration asserts that although cell penetrating peptides (CPPs) were known in the prior art, the majority were L-amino acids not fully D-amino acid peptides (para 8).
The disclosure asserts that most CPPs function by interacting with the cell membrane (para 9). The claimed peptides have the pseudosubstrates that specifically binds the protein kinase C zeta (PKCζ). Id. Applicant asserts that enzyme’s substrate interactions are well known to the enantiomer specific, referencing Milton et al (reference cited by Examiner but not relied upon; declaration at para 9). The declaration asserts that it was not predictable at the time of filing that retro-inversion to an all-D amino acid sequence would both preserve a specific binding to PKCζ and produce the desired transient modulation of tight junctions. Id.
Of note, Milton et al discuss D-amino acid HIV-1 protein, NOT a peptide, much less a CPP as instantly claimed. This reference was not relied upon in the 103 rejection.
The declaration asserts that conversion of L- to D- amino acids is well established in antimicrobial peptides for the benefit of increased resistance to proteolytic cleavage, but is only one strategy [of many] in the field of cell penetrating peptides (para. 10). The declaration asserts that retro-inversion [converting all amino acids from L- to D-] can cause severe cellular toxicity, citing Holm et al (Biochimica et BIophysica Acta 1808:1544-1551 (2011)). The declaration asserts that one reason for toxicity is the absence of reversibility which leads to extended cellular permeability. A key property of cell penetrating peptides to allow reversible cell and tissue penetration, to avoid the onset of toxicity. Id.
The declaration lists references cited in the IDS filed 1/26/2026 that provide other known peptide-engineering strategies for improving cell penetration were cell permeability without increasing toxicity, e.g. PEGylation, cyclization, N-terminal fatty acids (para. 10).
The declaration discloses that is the filing date of the instant application, “the outcome of retro-inverting the peptide taught by Conde to an all-D- amino acid sequence was unpredictable with respect to achieving transient tissue penetration and minimizing toxicity” that the combination of cited references does not indicate achieving such results (para. 11). The declaration asserts that in the field of cell penetrating peptides, retro-inversion to D- amino acids can induce toxicity and enzyme’s substrate interactions are stereospecific. Id. The declaration asserts that there are numerous alternative strategies for improving characteristics of cell penetrating peptides available and well documented in the literature. Id. Declaration asserts that the results described in the instant application are unpredictable and un-derivable from the combination of Conde and Martinez-Rodriguez (para 12).
Examiner Rebuttal
Examiner has reviewed and considered applicant’s arguments and the Borchard declaration, but is not persuaded.
With regard to regard to applicant’s assertions of examiner’s “assumptions”, examiner refers applicant to the entirety of the 103 rejection, which relies on a combination of Conde and Martinez-Rodriguez and the rationales set forth therein, not merely the “two assumptions” as indicated by applicant.
Conde et al teach peptides of formula (I) and pharmaceutically acceptable derivatives thereof, which peptides contain 3 to 15 amino acid residues and inhibit protein kinase C zeta (abstract). Specific peptides include SEQ ID NOs:3-5. Conde et al. show a preferred inhibitor peptide as Ala-Arg-Arg-Trp-Arg (SEQ ID NO 3) (Example 3; claim 4) with homology to the peptide of instant SEQ ID NO: 4 (ARRWR – all D-amino acids). Conde et al. teach an inhibitor peptide is further modified by myristoylation at the N-terminal amine group (p3, line 13-14), reading on (myristoylation)-ARRWR of the (p. 5,ll. 18-25 of instant specification). Conde expressly states at page 4, ll. 11-14: the amino acids may be either of the natural L-form or of the D-form or mixture e.g. a racemic mixture, of L- and D- forms.
Although Conde et al. taught a peptide Myr-ARRWR (SEQ ID NO:3) that can further include D-amino acids, the reference does not explicitly teach that all of the amino acids are D-amino acids [to give SEQ ID NO:4].
Martinez-Rodriguez is a review article discussing the importance of preparing peptides with D-amino acids in the pharmaceutical industry (abstract, title, pp. 1531, 1535-1540,1544) . The reference further teaches that D-amino acid-containing peptides have increased resistance to proteolytic cleavage and are therefore more stable. Id. In contrast, Applicant is minimizing the general overall teachings of inclusion of D-amino acids in therapeutic peptides to merely “antimicrobials and hormonal peptides”.
The following relates to applicant’s assertions relating to peptide stability and alleged “potential toxicity” of the claimed peptides comprising all D-amino acids (reply sect 1.3-1.4 and 1.6, declaration para 9-11). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., reversible tight junctions) are NOT recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, MPEP guidelines do not impose such experimentation as applicant appears to require (reply at p. 8).
In response to applicant's argument that the combination of references relates to improvement of the stability of the peptides via incorporation of D- amino acids as opposed to reversible tight junction modulators, the fact that the inventor has recognized another advantage [reversible tight junctions] which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant’s reliance on Holm et al (Biochimica et BIophysica Acta 1808:1544-1551 (2011)) for the assertion of “increased stability reduces reversibility, and reduces reversibility increases toxicity” (reply at pp. 3-6; declaration at paras 9-11) is misplaced.
Holm et al title- Retro-inversion of certain cell-penetrating peptides causes severe cellular toxicity.
Holm et al states:
Cell-penetrating peptides (CPPs) are relatively short, cationic and/ or amphipathic peptides that have successfully been exploited to convey a wide range of cargos into different cell-lines in vitro, as well as in vivo. The major advantages associated with this class of delivery vectors, apart from their high delivery efficacy, is that they generally display low toxicity and that there appear to be no size restraints in terms of cargo compounds that can be transported into cells using these peptides. One shortcoming, however, that has been realized in the last few years, is the frequent accumulation of CPPs in the endosomal compartments, which greatly reduces the bioavailability of the cargo molecules. Several different strategies have successfully been explored to overcome this problem, either by introducing chemical modifications in CPPs or by conjugating fusogenic peptides to CPPs. Another major issue that needs to be addressed is the rapid degradation of CPPs in the presence of serum. Almost all naturally occurring polypeptides are composed of L-amino acids and, consequently, the cellular proteolytic machinery does not recognize D-amino acids. Thus, substituting L- with D-amino acids in a peptide sequence increases its stability. This approach has proven successful for CPPs, e.g. polyarginine, pVEC, and penetratin.
Holm et al. at p. 1544. Emphasis added. Thus, Holm et al recognized the importance of incorporation of D-amino acids into cell penetrating peptides to improve peptide stability (e.g., the claimed peptides, as of 2011).
Hom et al further states:
The aim of our study was to increase the stability of a CPP (M918) designed in our lab, thereby making it a more potent transporter. Another CPP (p14Arf), previously reported by our group to have apoptogenic effects was also subjected to the RI modification in order to enhance its efficacy. The two most commonly used CPPs Tat and penetratin were studied in RI mode for comparison. The results indicate that cytotoxicity arises with RI-peptides above a certain length. Also the high number of hydrophobic amino acids in the peptide sequence might have a role in the induction of toxicity.
p. 1545. Table 1 discloses the peptides that were prepared in Holm et al. The shortest peptides assess in Holm were RI-Tat (retro-inversion HIV Tat peptide [CPP], all D- amino acids, 11 aa long) and RI-short penetratin (retro-inversion shortened CPP, all D- amino acids, 9 aa long). See Table 1.
Adverse toxic effects were observed for all the RI-peptides, except for RI-Tat. Since RI-Tat is only 11 amino acids long, we hypothesized that this could be one of the reasons for the observed difference in toxicity of the RI-peptides. We therefore synthesized a truncated version of RI-penetratin with only the first 9 amino acids, named RI short penetratin. This peptide was also nontoxic to the cells, suggesting that RI-peptides above a certain length cause these adverse effects. The importance of the peptide length on the cytotoxicity has been demonstrated before for e. g. polyarginine.
p. 1549. Emphasis added. Thus, Holm et al teach that the amino acid length of the CPP contributes to whether or not a given peptide has peptide toxicity.
The claimed peptides are 5 amino acids in length, shorter than the CPPs taught in Holm et al. Contrary to Applicant’s assertions, the skilled artisan- based on the teachings of teachings of Holm- would have expected that retro-inversion (incorporating all-D amino acids) of the peptides of Conde et al would yield peptides [of instant SEQ ID NOs:2 or 4] that were stable and non-toxic.
Contrary to applicant’s assertions, Martinez-Rodriguez does not “teach away” from incorporating D- amino acids into the peptides of Conde et al. It is further noted that just because something “may occur” [potential toxicity] cannot be conflated with something that will, in fact, occur, much less be a basis to stagnate progression of science of peptide therapeutics comprising D- amino acids.
The following relates to Applicant’s assertions that full stereoinversion is “unpredictable”, and references Milton et al and Fitzgerald et al (reply at p. 4; declaration at para 9 and 11). Milton et al and Fitzgerald et al are references that are cited but not relied upon. The instant 103 rejection stands on its own as set forth herein. The references cannot and are not relied upon for purposes of the rejection. Milton et al and Fitzgerald et al were previously presented
The references each teach a protein [not peptide] that incorporates all D-amino acids. Each reference further discloses that full enantiomers/mirror images/stereo-inversions were expected to/did have the same functional activity as the al L-amino acid equivalent protein. See section entitled “Relevant art not relied upon” below for specific details. The references were first presented in the office action mailed 10/30/2024 to further indicate that peptides and proteins comprising D-amino acids were known in the prior art, and that the overall trend in peptide therapeutics was towards incorporation of D- amino acids (see nonfinal office action mailed 10/30/2024 at pp. 15, 29-32).
With regard to “finite number of predictable solutions” and “arguments of counsel” (reply at section 1.5; declaration at para 10), the 103 rejection relates to a finite number of amino acids in the peptides [5 amino acids] and incorporating all-D amino acids into the peptides, not to other peptide engineering strategies. Examiner acknowledges applicant’s arguments and the declaration that other peptide engineering strategies, e.g., PEGylation, cyclization peptide stapling were known in the prior art. However, the instant 103 rejection relates to incorporation of D- amino acids based on the combination of teachings of Conde and Martinez-Rodriguez. Disclosure of other methodologies is extraneous to the instant rejection.
Contrary to the assertions set forth in the declaration, CPPs comprising D-amino acids were known in the prior art. Koren et al. (Trends in Molecular Medicine 18(7):385-393 (2012)- previously cited under Relevant art not relied upon) is a review article teaching that cell penetrating peptides (CPPs) have been shown to be powerful transport vector tool for the intracellular delivery of a large variety of cargoes through the cell membrane (abstract). The stability in vivo of CPPs is at risk until they reach their target. These peptides can be enzymatically cleaved by plasma enzymes and thus need to be sterically protected. The use of a protease-resistant D-form of the peptides instead of the naturally occurring L-amino acid form is a prominent strategy for CPP clinical usage (p 389). Thus, the prior art explicitly taught methods of improving CPP stability by incorporating D- amino acids into the CPP sequence. See also above, discussing Holm et al (Biochimica et BIophysica Acta 1808:1544-1551 (2011))- relating to short CPP peptides having all D-amino acids.
As noted in the instant office action, Conde expressly taught inclusion of D-amino acids. Martinez-Rodriguez et al further taught advantages of incorporating D- amino acid into peptides; e.g., increasing stability. The basis of the rejection is D-amino acids. Examiner reiterates, the claimed peptides have only 5 amino acids in each sequence. Thus, incorporating a D- amino acid at each position is obvious to try, and well within the realm of common knowledge and common sense of the skilled artisans as set forth in the above 103 rejection.
Conde teaches the peptide Myr-ARRWR (SEQ ID NO:3). Martinez-Rodriguez et al. is a review article discussing the advantages of including D-amino acids in a peptide sequence. The reference teaches that D-amino acid-containing peptides have increased resistance to proteolytic cleavage and are therefore more stable (pp. 1535-1540). Thus the skilled artisan would have been motivated to increase the stability of the peptides of Conde et al with all D-amino acids [Conde taught the peptides could comprise D-amino acids].
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.”
At the time of the invention, there had been a finite number of identified, predictable potential solutions to the design of a peptide taught by Conde et al. Conde et al. taught peptide of Myr-AKRWR (SEQ ID NO:3). This peptide has 5 amino acids. Thus, there are a finite number of FIVE amino acids to incorporate D-amino acids.
In view of these findings, it would have been obvious to prepare a peptide of Myr-AKRWR (SEQ ID) consisting of all D-amino acids. 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.
It would have been obvious to include the D-amino acids taught by Martinez-Rodriguez et al in the peptide of Conde et al in order to improve the stability of the peptide and increase proteolytic resistance. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Furthermore, MPEP guidelines require a “reasonable” expectation of success, there is no requirement of a guarantee of success. Conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP § 2143.02.
The rejection is maintained for at least these reasons and those previously made of record.
Claims 1 and 15-17 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Conde et al (WO 93/20101- previously cited) and Martinez-Rodriguez et al. (Chem Biodivers 7(6):1531-1548 (2010) - previously cited), as applied to claims 1 and 15-17 above, and further in view of Betts et al.(Bioinformatics for Geneticists pp. 289-316 (2003) - previously cited). The rejection is maintained from the office action mailed 9/24/2025.
The teachings of Conde et al and Martinez-Rodriguez et al. are set forth above.
Although the references teach a peptide of Ala-Arg-Arg-Trp-Arg (Conde et al SEQ ID NO:3), the N-terminus can have a fatty acid such as myristoyl, and the peptides can further comprise D- amino acids (p. 3, ll. 1-12; p. 4, ll. 11-12), the references do not expressly teach a peptide of Ala-Lys-Arg-Trp-Arg (instant SEQ ID NO:2), wherein Xaa5 is Lys.
Betts et al. is a review article teaching conservative amino acid substitutions that can preserve peptide/protein function and structure. Betts et al teach that arginine is a positively-charged, polar amino acid. It thus most prefers to substitute for the other positively-charged amino acid, lysine (p. 303).
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting arginine of Ala-Arg-Arg-Trp-Arg with lysine (Ala-lys-Arg-Trp-Arg) arginine and lysine are both explicitly taught as being positively-charged, polar amino acids. Therefore, these amino acids are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). A peptide of Myr-AKRWR (instant SEQ ID NO:2) wherein all amino acids are D-amino acids is rendered obvious.
Claims 1 and 15-17 are obvious in view of the teachings of the cited references.
Response to Arguments
Applicant traverses the rejection at p. 6 of the reply filed 1/23/2026. Applicant asserts the above rebuttal arguments for Martinez-Rodriguez et al which will not be restated here. Applicant asserts: The addition of Betts does not resolve [the alleged] deficiencies of the combination of Conde and Martinez-Rodriguez (p. 6).
Examiner has reviewed and considered Applicants arguments but is not persuaded. Please also see Examiner’s counter-augments above which are incorporated herein. The rejection is maintained for at least these reasons and those previously made of record.
Double Patenting- maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1 and 15-17 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26, 34, 36, 41, 42, and 46 of copending Application No. 17198285 (hereinafter referred to as “the ‘285 application”) in view of Martinez-Rodriguez et al. (Chem Biodivers 7(6):1531-1548 (2010)- previously cited). The rejection is maintained from the office action mailed 9/24/2025.
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn to a peptide of SEQ ID NOs:2 or 4. Claims 15-17 recite pharmaceutical compositions comprising at least one peptide and a pharmaceutically acceptable carrier, forms of the composition [ophthalmic, oral, nasal], and inclusion of an additional therapeutic compound or agent.
Claims 26, 34, 36, 41, 42, and 46 of the ‘285 application are drawn to a method for enhancing transient tissue permeabilization of a therapeutically effective agent in a subject suffering from the disease or disorder, the method comprising (a) selecting a peptide that consists of Myr-ARRWR (SEQ ID NO: 2) or Myr-AKRWR (SEQ ID NO:3), (b) selecting a dosage of the peptide in an amount of 5 µg or less to enhance transient tissue permeabilization of the therapeutically effective agent when combined with the peptide compared to tissue permeabilization of the therapeutically effective agent when administered in the absence of the peptide; (c) selecting a dosage of the therapeutically effective agent wherein the transient tissue permeabilization of the therapeutically effective agent is enhanced when combined with the peptide compared to the tissue permeabilization of the therapeutically effective agent when administered in the absence of the peptide; and(d) administering the peptide and the therapeutically effective agent in a combination sufficient to enhance tissue permeabilization of the therapeutically effective agent compared to tissue permeabilization of the therapeutically effective agent when administered in the absence of the peptide.
Claims 34 and 36 of the ‘285 application recite that the disease is cancer and inclusion of an anticancer agent. Claims 41 and 42 of the ‘285 application recite functional language of the peptides - enhance tissue permeabilization - redistribution of occluding inside a cell/inducing transient opening of tight junction between adjacent cells. Claims 46 of the ‘285 application recites therapeutically effective amounts of the peptide.
The claims of the ‘285 application teach peptides Myr-ARRWR (SEQ ID NO: 2) and Myr-AKRWR (SEQ ID NO:3), the claims do not explicitly teach that all of the amino acids are D-amino acids.
Instant SEQ ID NO:2 (Myr-akrwr) and SEQ ID NO:4 (Myr-arrwr) wherein each of the amino acid positions is a D- amino acid.
Martinez-Rodriguez et al. is a review article discussing the advantages of including D-amino acids in a peptide sequence. The reference teaches that D-amino acid-containing peptides have increased resistance to proteolytic cleavage and are therefore more stable (pp. 1535-1540).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a peptide of Myr-ARRWR (SEQ ID NO:2 of the ‘285 application, instant SEQ ID NO:4 with D- amino acids) or Myr-AKRWR (SEQ ID NO:3 of the ‘285 application, instant SEQ ID NO:2 with D- amino acids), as taught by ‘285 application claims, comprising all D-amino acids in view of the teachings of Martinez-Rodriguez et al. The skilled artisan would have been motivated to do so because the ‘285 application claims taught comprising specific peptides of Myr-ARRWR or Myr-AKRWR. The skilled artisan would have had a reasonable expectation of success because Martinez-Rodriguez et al. specifically taught including D-amino acids in a peptide sequence increased peptide stability. Instant SEQ ID NOs:2 and 4 have the same amino acid sequence as SEQ ID NOs:2-3 of the ‘285 application.
The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969). 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 teachings of the ‘285 application claims and Martinez-Rodriguez et al.
As noted above, the claims of the ‘285 application taught peptides of Myr-ARRWR (SEQ ID NO: 2) and Myr-AKRWR (SEQ ID NO:3), but the claims do not explicitly teach that all of the amino acids are D-amino acids. However, this difference is obvious according to the rationale in MPEP § 2143.01(E): "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success. At the time of the invention, there was a recognized problem or need in the art. Specifically, peptides comprising L-amino acids were subject to proteolytic cleavage and therefore less stable therapeutics To overcome this problem, Martinez-Rodriguez et al. teaches modification of peptides via incorporation of D-amino acids.
At the time of the invention, there had been a finite number of identified, predictable potential solutions to the design of a peptide taught by the ‘285 application. The claims of the ‘285 application taught peptide Myr-ARRWR (SEQ ID NO: 2) and Myr-AKRWR (SEQ ID NO:3). The peptides each have 5 amino acids. Thus, there are a finite number of amino acids to incorporate D-amino acids.
In view of these findings, it would have been obvious to prepare a peptide of Myr-AKRWR or Myr-ARRWR (SEQ ID NO:2 or 4) consisting of all D-amino acids. The resulting peptide would satisfy all of the limitations of claim 1, . 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.
It would have been obvious to include the D-amino acids taught by Martinez-Rodriguez et al in the peptides of the ‘285 application in order to improve the stability of the peptide and increase proteolytic resistance. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Accordingly, peptides of claims 1 and 15-17 are rendered obvious and can be used in the methods claims of the ‘285 application.
Response to Arguments
Applicant traverses the rejection at pp. 6-7 of the reply filed 1/23/2026. Applicant’s rebuttal arguments are presented above under the 103 rejection as relating to the alleged deficiencies of Martinez-Rodriguez et al.
Please see Examiner’s counter-augments under the 103 rejection above which are incorporated herein. The rejection is maintained for at least these reasons and those previously made of record.
Examiner Comment
Applicants are reminded of their right to appeal the examiner's rejections to the Board of Appeals and Interferences.
Relevant art not relied upon
The following article was cited in Martinez-Rodriguez as reference 112.
Dooley et al. (Science 266:2019-2022 (1994)- previously cited) teach the all D-amino acid peptides Ac-rfwink-NH2, an opioid peptide having high selectivity for mu opioid receptor (abstract, p. 2021). Dooley et al states at p. 2021:
Unlike peptides comprised of naturally occurring L-amino acids, a D- amino acid peptides will not be degraded by proteases. Therefore, peripherally administered Ac-rfwink-NH2 can be expected to remain intact, which will increase both the amount of peptides crossing the blood brain barrier and resulting analgesia. Although the potency of Ac-rfwink-NH2 in the guinea pig ileum assay was lower than that of PLO17, the ability of Ac-rfwink-NH2 to cross the blood brain barrier and long duration of action makes us peptides of interest for in vivo studies.
Thus, despite a lower binding efficiency compared to the L-form, increased stability of the all D-amino acid Ac-rfwink-NH2 was a more desired and advantageous property of the peptide.
Examiner notes that similar to the claimed peptides of instant SEQ ID NOs:2 and 4, the peptide of Dooley is a short peptide of 6 amino acids in length and comprises an acyl moiety at the N-terminus.
Koren et al. (Trends in Molecular Medicine 18(7):385-393 (2012)- previously cited) is a review article teaching that cell penetrating peptides (CPPs) have been shown to be powerful transport vector tool for the intracellular delivery of a large variety of cargoes through the cell membrane (abstract). Intracellular delivery of plasmid DNA (pDNA), oligonucleotides, small interfering RNAs (siRNAs), proteins and peptides, contrast agents, drugs, as well as various nanoparticulate pharmaceutical carriers (e.g., liposomes, micelles) has been demonstrated both in vitro and in vivo. Id. The stability in vivo of CPPs is at risk until they reach their target. These peptides can be enzymatically cleaved by plasma enzymes and thus need to be sterically protected. The use of a protease-resistant D-form of the peptides instead of the naturally occurring L-amino acid form is a prominent strategy for CPP clinical usage (p 389).
Milton et al. (Science 256:1445-1448 (1992)- previously cited) teach D and L forms of the enzyme HIV-1 protease have been prepared by total chemical synthesis. The two proteins had identical covalent structures. However, the folded protein-enzyme enantiomers showed reciprocal chiral specificity on peptide substrates. These data imply that the folded forms of the chemically synthesized D- and L-enzyme molecules are mirror images of one another in all elements of the three-dimensional structure. Enantiomeric proteins are expected to display reciprocal chiral specificity in all aspects of their biochemical interactions (abstract). D-proteins are expected to be long-lived in vivo (in an L-protein biosphere) because they would be resistant to naturally occurring proteases that would in general attack only proteins made up of L-amino acids. D-Proteins may also be nonimmunogenic (p. 1447). D-Protein molecules have other potentially practical applications. The total chemical synthesis of proteins should considerably increase the utility of this approach to the preparation of protein enantiomers. Id.
Fitzgerald et al (J. Am. Chem. Soc. 117:11075-11080 (1995)- previously cited) teach native L-form and the mirror image D-form of the enzyme 4-oxalocrotonate tautomerase (40T) were prepared by total chemical synthesis. Our results indicate that both enzymes were efficient catalysts and demonstrate, as expected, that the achiral substrate 2-hydroxymuconate (2) was processed with equal efficiency by either the d- or the L-enzyme (abstract). Our kinetic, structural, and stereochemical data for these synthetic enzymes reveal that they fold to form active enzyme complexes and that, as expected, the enzyme enantiomers are equally active on the achiral substrate 2 (p. 11078).
Falciani et al (PLOS One 7(10):e46259 pp. 1-8 (2012)- previously cited) teach synthesis and comparison of M33 antimicrobial peptide consisting of L- amino acids and D-amino acids (M33-D) (abstract). The peptide consisting of D-amino acids showed 4 to 16-fold higher activity against Gram positive pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, than the original peptide, while retaining strong activity against Gram-negative bacteria. The antimicrobial activity of both peptides was influenced by their differential sensitivity to bacterial proteases. The better activity shown by M33-D against S. aureus compared to M33-L was confirmed in biofilm eradication experiments where M33-L showed 12% activity with respect to M33-D, and in vivo models where Balb-c mice infected with S. aureus showed 100% and 0% survival when treated with M33-D and M33-L, respectively. M33-D appears to be an interesting candidate for the development of novel broad-spectrum antimicrobials active against bacterial pathogens of clinical importance.
The peptide consisting of D-amino acids was more stable and functionally effective and the peptide consisting of all L-amino acids.
The prior art taught incorporation of D-amino acids into peptides which increased stability and protease resistance.
Conclusion
No claims are allowed.
Claims 1, 15-17, 19, 20, and 25-29 are pending. Claims 19, 20, and 25-29 remain withdrawn.
Claims 1 and 15-17 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654