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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant's arguments filed 8/20/2026, with respect to the claim rejections under 35 U.S.C. 103, have been fully considered but they are not persuasive.
Applicant’s position is that 1) Johnson does not disclose myristoyl can be added to the N-terminus of P-L-TAT nor the use of both TAT and myristoyl group together with its PKC modulary peptide and 2) the claimed compounds exhibit unexpected results.
Regarding 1), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Johnson teaches capping the amino and/or carboxy termini of the peptides to increase hydrophobicity. This teaching effectively reads on adding an N- or C-terminal modification to the peptide and provides a motivation to do so, namely, to further protect the peptide from protein degradation (see [0076] of Johnson, cited in prior Office Action). Therefore, it would be obvious to add a capping moiety such as myristoyl to the N-terminus of the peptide taught by Johnson. This teaching, combined with the knowledge that one skilled in the art could easily rearrange two protein domains connected via a linker from P-L-TAT into TAT-L-P renders the instant claims obvious; see below for more in art rejections.
Regarding 2), per MPEP 716.02(C)(II), “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).” In the instant case, Figure 3 demonstrates a significant reduction in infarct size of rat hearts in response to treatment with the claimed Myr-TAT-PCKε inhibitor. However, in view of the prior art, these results are not unexpected. Individually, the cell penetrating peptide TAT and myristoyl are known in the art to improve the functionality of a conjugate by encouraging entry or absorption into cells; see, for instance, Mochly-Rosen ([0014]) and Lindon ([0020]), respectively. Consequently, one of ordinary skill in the art would reasonably expect the combination of the two moieties into one peptide to exhibit significant functional improvement compared to a peptide conjugated to only TAT or only to myristoyl. As a result, the claim rejections under 35 U.S.C. 103 have been maintained/modified herein.
Applicant’s arguments, filed 8/20/2026, with respect to the double patenting rejections have been fully considered and are persuasive. The rejections have been withdrawn in view of the amended claims.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-12, drawn to a compound comprising a peptide having the structure of Formula I, in addition to the species of a PKCε inhibitor, in the reply filed on 11/17/20205 is acknowledged. The traversal is on the ground(s) that 1) a lack of unity of invention has not been shown as Johnson does not teach a compound of Formula I and 2) no rationale was provided for the species election requirement. This is not found persuasive.
First and most importantly, as stated in the prior Restriction/Election requirement, a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories (1)-(5), as provided in 37 CRF 1.475(b) (see Restriction/Election requirement, Pg 4-5). The inventions as listed in Groups I-III do not constitute a combination of categories of inventions in accordance with 37 CFR 1.475(b) because the claims are drawn to two products (Groups I and II) and one process of use (Group III). Therefore, the claims are not drawn only to one of the combinations of categories and, thus, lack unity of invention. This is sufficient to break unity of invention and unity of species.
Regarding 1) and 2), these points are moot given that unity of invention was first and foremost broken based upon the fact that the instant claims do not meet the requirements of 37 CRF 1.475(b).
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1, 10, and 13-20 are pending. Claims 13-20 are withdrawn. Claim 1 is currently amended.
Priority
The instant application is the 371 national stage entry of PCT/US2021/023943, filed 3/24/2021, which claims priority to provisional applications 63017488, filed 4/29/2020, and 62994098, filed 3/24/2020. The priority date of 3/24/2020 is acknowledged.
Claim Interpretation
Claims 1 and 10 each recite limitations wherein a certain part of the claimed structure has an amino acid sequence (emphasis added). This claim is being interpreted as a peptide comprising the component of Formula I, wherein a peptide or protein encompassing or containing the entirety of the component of Formula I meets the limitation of the claim. Conversely, smaller fragments encompassed by the component of Formula I (i.e., dipeptides) are being interpreted as not meeting the limitations of the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 10 recites that TAT, the linker, and the PKCε inhibitor form a peptide with at least about 80% identity to one of SEQ ID NO: 15, 18, 21, 24, 25, and 27-31. However, SEQ ID NO: 4, as required by claim 1, only appears in SEQ ID NO: 18 and 27. Additionally, none of SEQ ID NO: 15, 18, 21, 24, 25, and 27-31 comprise any of SEQ ID NO: 9-14. In other words, SEQ ID NO: 15, 18, 21, 24, 25, and 27-31 are broader than their parent claim, claim 1, because they do not include SEQ ID NO: 4 and/or one of SEQ ID NO: 9-14. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
First rejection
Claim(s) 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al. (US 2010/0311671 A1, published 12/9/2010; cited on IDS filed 9/23/2022), as evidenced by Chen et al. (protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013 Oct;65(10):1357-69.).
Johnson teaches methods for transdermal delivery of PKC modulatory peptides (Abstract). The PKC modulatory peptide can be modified by attachment to another peptide or to a linker to form a fusion peptide or a conjugate. As an example, the peptide modulator may be linked or otherwise conjugated to a second peptide by an amide bond from the C-terminal of one peptide to the N-terminal of the other peptide. The peptide attached to the PKC modulatory peptide can be a peptide that functions to increase the cellular uptake of the peptide inhibitors, such as a CPP. One CPP contemplated by Johnson is Transactivating Regulatory Protein (TAT)-derived transport polypeptide ([0063, 0065]). The linker is an amino acid linker and can be, for instance, “GG” or any number of residues (2-8), where glycine is merely exemplary ([0067]).
Johnson states that examples and discussions herein that are particular to a specific PKC modulatory peptide are merely exemplary of the peptides for any given PKC isozyme. With this understanding, and based on the description above of exemplary cell penetrating peptides and approaches for linking to a PKC modulatory peptide, a skilled artisan can readily envision conjugates for use in the methods described herein. As an example, Johnson teaches SEQ ID NO: 14, which consists of the formula P-L-TAT, wherein P is a PKC peptide modulator, L is a peptide linker, and TAT is the CPP. The sequence of SEQ ID NO: 14 is EAVSLKPTGGYGRKKRRQRRR (Sequence Listing), wherein “EAVSLKPT” is a PKCε inhibitor identical to the instant SEQ ID NO: 4, “GG” is an amino acid linker L, and “YGRKKRRQRRR” is TAT identical to the instant SEQ ID NO: 1 ([0067]).
Johnson also teaches that PKC modulatory peptides or conjugates may be targeted by proteases in the body for degradation. One approach to protecting peptides from proteolytic degradation involves capping the amino and/or carboxy termini of the peptides, wherein capping refers to the introduction of a blocking group to the terminus via a covalent modification without decreasing the biological activity of the peptide. Acetylation of the amino termini is one method of protecting the peptides from proteolytic degradation but other capping moieties are also possible, including myristoyl ([0076]).
In summary, Johnson teaches a peptide conjugate of the general formula P-L-TAT that can be further modified by introducing a capping moiety, such as a myristoyl group, to the N-terminus of the peptide. Johnson does not explicitly teach a peptide conjugate of formula I, Myr-TAT-L-P, nor that the linker comprises one of the instant SEQ ID NO: 9-14.
However, it would have been prima facie obvious to try rearranging the relative order of TAT and P, thereby producing a compound of formula TAT-L-P. At the time of filing, the art recognized that connecting peptides or peptide domains to each other through linkers allowed the fusion protein to retain the individual structure and functionalities of the peptides or peptide domains, as evidenced by Chen (see Introduction, Pg1; 3.1 Flexible linkers, Pg 4-5). Moreover, Johnson also indicates that a skilled artisan can readily envision additional conjugates based upon the exemplary cell penetrating peptides and approaches for linking to a PKC modulatory peptide. One of ordinary skill in the art would recognize that a fusion peptide comprising two independent peptides/peptide domains connected by a single linker could only be combined in two different ways; moreover, one would recognize that after trying the orientation taught by Johnson, there would only be one other possible combination, the instant formula I as recited in claim 1. Therefore, it would be obvious to try this additional combination, based upon the teachings of Johnson as evidenced by Chen.
Moreover, per MPEP 2144.04(VI)(C), rearrangement of parts is one legal precedent recognized by the courts as directed to common practices that normally require only ordinary skill in the art and are considered routine expedients: “In re Japikse, 181 F.2d 1019, 86 USPQ 70 (CCPA 1950) (Claims to a hydraulic power press which read on the prior art except with regard to the position of the starting switch were held unpatentable because shifting the position of the starting switch would not have modified the operation of the device.); In re Kuhle, 526 F.2d 553, 188 USPQ 7 (CCPA 1975) (the particular placement of a contact in a conductivity measuring device was held to be an obvious matter of design choice).” In the instant case, the parts are TAT and P, which can easily be rearranged and connected by a single linker L to arrive at the instant formula I; Johnson teaches as much by disclosing that one skilled in the art can easily envision other protein conjugates that could be derived from the teachings at hand.
Further, Johnson teaches adding a lipid-based group to the N-terminus of such peptides in order to protect them from protein degradation; therefore, it would be obvious to further modify the peptide TAT-L-P by adding a myristoyl group to the N-terminus, thus producing the instant formula I. One skilled in the art would be motivated to do so in order to better protect the fusion peptide from protein degradation. One would have a reasonable expectation of success as Johnson established this as viable strategy to avoid protease activity.
Additionally, as stated above, Johnson does teach that an amino acid linker can be, for instance, “GG” or any number of residues (2-8), where glycine is merely exemplary ([0067]). Thus, it would be obvious to one skilled in the art to establish a peptide linker sequence of at least GGGG (SEQ ID NO: 10); Chen further evidences this by indicating that Gn, where n is the number of amino acids, is an ideal peptide linker based on its size and flexibility (Table 2 on Pg 29).
Consequently, it would be obvious to generate a peptide comprising myristoyl linked to SEQ ID NO: 1 linked to SEQ ID NO: 10 linked to SEQ ID NO: 4.
Regarding claim 10, the rearrangement of the individual components of SEQ ID NO: 14 of Johnson with the addition of the N-terminal myristoyl group, renders the instant SEQ ID NO: 27 of claim 10 obvious. It also renders the instant SEQ ID NO: 18 obvious, which exhibits >80% sequence identity to the rearranged SEQ ID NO: 14 of Johnson.
Claim(s) 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Mochly-Rosen et al. (US 20070066526 A1, published 3/22/2007; cited on IDS filed 9/23/2022) in view of Lindon (US 20070148628 A1, published 6/28/2007) and Chen et al. (protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013 Oct;65(10):1357-69.).
Mochly-Rosen teaches a method for reducing risk of stroke in a subject with hypertension by administering an inhibitor of delta PKC to the subject (Abstract). Mochly-Rosen teaches that a therapeutically effective amount of the inhibitor is the quantity required to increase cerebral blood flow and/or reduce cell, tissue, or organ damage or death that occurs due to stroke and/or reperfusion following recanalization after and ischemic stroke ([0188]).
Mochly-Rosen also teaches Example 2 wherein rats were administered SEQ ID NO: 88, which is a conjugate thereof identical to the instant SEQ ID NO: 18 that mirrors TAT-L-P of the instant formula I, prior to induction of stroke ([0148]; Sequence Listing); in other words, SEQ ID NO: 88 consists of the instant SEQ ID NO: 1 linked to the linker “CC” linked to SEQ ID NO: 4. Administration of SEQ ID NO: 88 improves the survival of rats after induction of stroke relative to saline or TAT alone (Figure 5).
Mochly-Rosen does not teach the addition of a myristoyl group to the N-terminus nor that the linker is one of SEQ ID NO: 9-14.
Lindon teaches solutions and peptides for preservation, perfusion, and/or reperfusion of an organ, especially the heart, for transplantation. The solution contains peptide inhibitor(s) of protein kinase C ε (PKC ε). Methods for using the inventive solution are also disclosed, including methods for protecting an ischemic organ from damage, for attenuating organ dysfunction after ischemia, for maintaining nitric oxide release and/or inhibiting superoxide release in an ischemic organ, and for protecting an organ from damage when isolated from the circulatory system (Abstract).
Lindon teaches that peptide PKCε inhibitors can be myristoylated at the N-terminus to further improve absorption into cells of the organ ([0020]).
Chen teaches flexible linkers often used in fusion proteins are generally composed of small, nonpolar (e.g., Gly) or polar (e.g. Ser or Thr) amino acids. The small size of these amino acids provides flexibility and allows for mobility of the connecting functional domains. The commonly used flexible linkers have sequences consisting of primary stretches of Gly and Ser residues (“GS” linker), such as (Gly-Gly-Gly-Gly-Ser)n, where the copy number “n” can adjust the length of the linker sequence “n” (Pg 4, paragraphs 2 and 3). Table 2 of Chen also indicates that (G)n is also another common flexible linker (Pg 29). Where n =4 results in a “Gly-Gly-Gly-Gly” linker which is equivalent to the instant SEQ ID NO: 10.
Thus, regarding claim 1, Mochly-Rosen teaches a peptide conjugate comprising the formula TAT-L-P, wherein P is a PKCε peptide inhibitor. Lindon teaches that PKCε peptide inhibitors can be further improved by adding a myrstioyl group to the N-terminus of the peptide. Based on these teachings, it would be prima facie obvious to add the myristoyl group to the N-terminus of the peptide conjugate of general formula TAT-L-P taught by Mochly-Rosen. One skilled in the art would be motivated to do so in order to improve the absorption of the peptide taught by Mochly-Rosen into the cells of organs in need thereof. One would have a reasonable expectation of success as Lindon previously established that myristoylation of PKCε inhibitors improved their activity in methods of protecting organs after ischemic events.
Further, it would be obvious to one skilled in the art to substitute the peptide linker “CC” taught by Mochly-Rosen for the linker GGGG (instant SEQ ID NO: 10) taught by Chen. One skilled in the art would be motivated to do so because one would recognize that it would be functionally interchangeable with the “CC” linker, thus making it obvious to try. One would have a reasonable expectation of success given that flexible peptide linkers are known to preserve individual domain functionality within a given fusion protein. Thus, it would be obvious to generate a peptide comprising myristoyl linked to SEQ ID NO: 1 linked to SEQ ID NO: 10 linked to SEQ ID NO: 4.
Regarding claim 10, as stated above, Mochly-Rosen teaches SEQ ID NO: 88 which is 100% identical to the instant SEQ ID NO: 18 and >80% identical to the instant SEQ ID NO: 27.
Prior Art Cited but not Referenced
MacLean et al. (WO 2008089494 A2, published 7/24/2008) teaches modified εPKC inhibitory peptides, methods of generating such peptides, and method for using εPKC inhibitory peptides for the treatment of pain (Abstract), including the peptide KP-1678 which consists of Ac-EAVSLKPTGGYGRKKRRQRRR-NH2 (Pg 15, lines 12-14). MacLean does not teach N-terminal myristoylation. However, rearrangement of the above sequence (MPEP 2144.04(VI)(C)) in view of Lindon would render the instant claims 1 and 10 obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
