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 .
Status of the application
Please note that for internal reasons to USPTO, this application has been reassigned.
Receipt of applicant’s remarks and claim amendments filed on 07/01/2026 are acknowledged.
In light of claim amendments, previous 112(b) rejection is withdrawn.
However, applicants’ arguments for the previous 103 rejection and nonstatutory double patenting rejections are found not persuasive. Accordingly, the previous rejections are maintained. Please see the examiners response to applicants arguments below.
A new Claim Objection and 112(b) rejection are also made.
Response to Arguments
Applicants’ main argument is that applicant respectfully notes that the problem to be solved by the present claims can be stated as that of providing alternative stapled peptides with advantageous binding properties. This problem is solved by the peptides provided in claim 1, which have the position of the hydrocarbon stable closer to the Beclin 1-peptide binding interface, leading to enhanced binding affinity by ~10-30 fold. Thus, as shown by the affinity data in the present application, the peptides of SEQ ID NO..
In Table 2, the position of R8 or S5 is same for all sequences, other than SEQ ID NO:78. There is no comparative data for the same sequence, with varying the positions of R8 and S5. The data shown is nothing but replacing various amino acids with other amino acids in the peptides and its effects on Kd.
As explained in the rejection, Zhao et al. (381) teaches that introducing the hydrocarbon link at a different position as compared to that of the instant application. Zhao et al. (381) further teach that the hydrocarbon stapled peptide of the reference comprises unnatural amino acids at any positions i and i+7, and in the case of positions 197 and 204, these unnatural amino acids are linked by means of hydrocarbons that stabilize the α-helical structure of Beclin-1 (see SEQ ID NOs: 1-12 and [0084]).
Though Zhao et al (381) do not show data, and it does not mean that the properties of peptides of Zhao differ from applicants claimed peptides, since applicants response failed to compare the peptides of Zhao with claimed peptides. In other words, the peptides of Zhao are expected to show similar Kd values, absent evidence to the contrary.
The compared data with SP4 is not relevant, since its sequence differs from the claimed sequence.
Claim Objections/Sequence Compliance
Claims 1 and 4 are objected to because of the following informalities: 37 CFR 1.821(d) states that where the claims recite a sequence the sequence identifier (SEQ ID NO) must be included. The applicants have provided a sequence listing, but have not included the corresponding sequence identifiers in claims.
Appropriate correction is required.
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.
Claims 1-2 and 4-5 are 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.
In claims 1 and 4, the cited “including a sequence of RLIQELEDVEKNRKV” is not clear. Is this sequence in addition to 191-205 of Beclin 1? Also, it is not clear what is excluded?
Is claimed fifth and twelfth amino acid residues pointing to the fragment of sequence residues from 191-205 of Beclin 1 or Beclin 1-targeting stapled peptide?
There are several “comprises” in the claim language.
Are SEQ ID NO: 21 and 32 part of staple peptide in addition to 191-205 of Beclin 1 or applicants intend to say “select staple peptide is selected from the group consisting of SEQ ID NO:21 and SEQ ID NO:32”?
Claims 2 and 5 recite R8 residue and S5 residue, though specification defined these, but it would be clearer if claims define these in the claim language. Further, it is not clear where exactly these are located, specifically, with in the 191-205 fragment or outside of this fragment, since in the preamble the product recites term “comprises”.
Therefore, the metes and bounds of claims are not clear and so, claims are rendered indefinite.
Claim Interpretation
Claims 1 and 4 are interpreted with the following claim language:
A Beclin 1-targeting stapled peptide comprises a peptide fragment of Beclin 1 and a hydrocarbon staple;
wherein peptide fragment of Beclin 1 has at least 66.7% sequence identical to amino acid residues 191- 205 of Beclin 1 (RLIQELEDVEKNRKV or SEQ ID NO:77);
wherein a fifth amino acid residue and a twelfth amino acid residue of the peptide fragment of Beclin 1 are connected by the hydrocarbon staple to stabilize an a-helical structure of the stapled peptide; and
wherein the peptide fragment of Beclin 1 is selected from the group consisting of SEQ ID NO.21 and SEQ ID NO.32.
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.
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 1-2 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180002381 A1, hereinafter Zhao et al. (381).
With regard to claim 1, Zhao et al. (381) teach designed peptide analogs that promote autophagy by specifically targeting the Beclin1-Vps34 complex (see [0003]). More specifically, they disclose a hydrocarbon-stapled polypeptide, wherein the hydrocarbon-stapled polypeptide comprises an amino acid sequence that is at least 85% identical to amino acid residues 191-205 of rat Beclin 1 (SEQ ID NO: 17 of the reference: RLIQELEDVEKNRKV), or amino acids 193-207 of human Beclin 1 (SEQ ID NO: 18 of the reference: RLIQELEDVEKNRKI) (see [0013]), thereby meeting the limitation that the stapled peptide is at least 66.7% identical to the amino acid residues 191-205 of Beclin 1. They further teach that a hydrocarbon staple 13 carbons in length is introduced to link residues 197 and 204 of the stapled peptide based on the 191-205 residues of Beclin 1 (see [0084]). This link is introduced to stabilize the α-helical structure of the Beclin-1 and modulate protein-protein interactions without interfering with binding (see [0098], [0101]), providing a clear motivation to introduce the hydrocarbon connection. For this invention, the α-helical segment corresponding to residues 191-205 within the Beclin 1 coil domain was used and modified by substituting the residues at positions 191, 194, 195, 201 and 205 (see [0084]). Zhao et al. (381) do, however, introduce the hydrocarbon link at a different position as compared to that of the instant application, as the hydrocarbon of their invention links unnatural amino acid positions 197 and 204 as opposed to 195 and 202 (see SEQ ID Nos: 1-12 and [0084]). Zhao et al. (381) further teach that the hydrocarbon stapled peptide of the reference comprises unnatural amino acids at any positions i and i+7, and, as discussed above, in the case of positions 197 and 204, these unnatural amino acids are linked by means of hydrocarbons that stabilize the α-helical structure of Beclin-1 (see SEQ ID NOs: 1-12 and [0084]). In other words, Zhao et al. (381) show that linking unnatural amino acids in positions i and i+7 within the range of positions 191-205, specifically positions 197 and 204, provides benefits in stabilizing the α-helical structure of Beclin 1, and they further suggest substituting unnatural amino acids at any i and i+7 positions within positions 191-205 (see [0084]). This provides a clear motivation to try to link any of the unnatural amino acid positions between 191-205 according to i and i+7 with a reasonable expectation of α-helical stabilization as evidenced by linking unnatural amino acid positions 197 and 204 with hydrocarbons. Given that the embodiments of the invention utilize modified positions of 191-205 of Beclin-1 (see [0084]), there are only eight possible connections/pairs between positions 191-205 that fit the requirement of linking positions i and i+7. Namely, positions 191-198, 192-199, 193-200, and so on through 198-205. Given the beneficial results in stabilizing the α-helical structure of Beclin-1 and the very limited possible positions to link within positions 191-205 following i and i+7, it would have been obvious to one having ordinary skill prior to the effective filing date of the instant application to try to link the fifth and twelfth amino acids in the residues 191-205 with a reasonable expectation of stabilizing the α-helical structure.
With regard to claim 2, Zhao et al. (381) disclose that the hydrocarbon stapled peptide contain (R)-2-amino-2-methyl-9-decenoic acid residues and (S)-2-amino-2-methyl-6-heptenoic acid residues (see SEQ ID NOs: 1-12 in the sequence listing of the reference). Zhao et al. (381) also explicitly teach that the stapled peptide comprises “R8” and “S5” residues (see Stapled peptide (I)).
With regard to claim 4, as discussed above, Zhao et al. (381) teach the hydrocarbon stapled peptide discussed above, and they also teach its integration into a pharmaceutical composition (see [0068]).
With regard to claim 5, as discussed above, Zhao et al. (381) disclose that the hydrocarbon stapled peptide contain (R)-2-amino-2-methyl-9-decenoic acid residues and (S)-2-amino-2-methyl-6-heptenoic acid residues (see SEQ ID NOs: 1-12 in the sequence listing of the reference). Zhao et al. (381) also explicitly teach that the stapled peptide comprises “R8” and “S5” residues (see Stapled peptide (I)).
Double Patenting
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 examine1 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2 and 4-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10,618,939 B2, hereinafter Zhao et al. (939) in view of US 20180002381 A1, hereinafter Zhao et al. (381).
With regard to claim 1, Zhao et al. (939) claim a hydrocarbon-stapled polypeptide designed to target Beclin 1 selected from the group comprising SEQ ID Nos: 1-12 (see claim 1). Zhao et al. (939) do not, however, explicitly claim which amino acids are connected by the hydrocarbons.
As discussed above, Zhao et al. (381) teach designed peptide analogs that promote autophagy by specifically targeting the Beclin1-Vps34 complex (see [0003]). More specifically, they disclose hydrocarbon-stapled polypeptides (SEQ ID Nos: 1-12), wherein the hydrocarbon-stapled polypeptide comprises an amino acid sequence that is at least 85% identical to amino acid residues 191-205 of rat Beclin 1 (SEQ ID NO: 17 of the reference: RLIQELEDVEKNRKV), or amino acids 193-207 of human Beclin 1 (SEQ ID NO: 18 of the reference: RLIQELEDVEKNRKI) (see [0013]). Here, SEQ ID Nos: 1-12 of Zhao et al. (939) are identical to SEQ ID Nos: 1-12 of Zhao et al. (381), so they similarly meet the limitation of being 85% identical to Beclin 1 (see SEQ ID NOs: 1-12 of Zhao et al. (381) and Zhao et al. (939). Zhao et al. (381) further teach that a hydrocarbon staple 13 carbons in length is introduced to link residues 197 and 204 of the stapled peptide (see [0084]). This link is introduced to stabilize the α-helical structure of the Beclin-1 and modulate protein-protein interactions without interfering with binding (see [0098], [0101]), providing a clear motivation to link the amino acid positions suggested by Zhao et al. (381). For this invention, the α-helical segment corresponding to residues 191-205 within the Beclin 1 coil domain was used and modified by substituting the residues at positions 191, 194, 195, 201 and 205 (see [0084]). Zhao et al. (381) do, however, introduce the hydrocarbon link at a different position as compared to that of the instant application, as the hydrocarbon of their invention link unnatural amino acid positions 197 and 204 as opposed to 195 and 202 (see SEQ ID Nos: 1-12 and [0084]). Zhao et al. (381) further teach that the hydrocarbon stapled peptide of the reference comprises unnatural amino acids at any positions i and i+7, and, as discussed above, in the case of positions 197 and 204, these unnatural amino acids are linked by means of hydrocarbons that stabilize the α-helical structure of Beclin-1 (see SEQ ID NOs: 1-12 and [0084]). In other words, Zhao et al. (381) show that linking unnatural amino acids in positions i and i+7 within the range of positions 191-205, specifically positions 197 and 204, provides benefits in stabilizing the α-helical structure of Beclin 1, and they further suggest substituting unnatural amino acids at any I and i+7 positions within positions 191-205 (see [0084]). This provides a clear motivation to try to link any of the positions between 191-205 according to i and i+7 with a reasonable expectation of α-helical stabilization as evidenced by linking unnatural amino acid positions 197 and 204 with hydrocarbons. Given that the embodiments of the invention utilize modified positions of 191-205 of Beclin-1 (see [0084]), there are only eight possible connections/pairs between positions 191-205 that fit the requirement of linking positions i and i+7. Namely, positions 191-198, 192-199, 193-200, and so on through 198-205. Given the beneficial results in stabilizing the α-helical structure of Beclin-1 and the very limited possible positions to link within positions 191-205 following i and i+7, it would have been obvious to one having ordinary skill prior to the effective filing date of the instant application to try to link the fifth and twelfth amino acids in the residues 191-205 with a reasonable expectation of stabilizing the α-helical structure. In other words, given that Zhao et al. (939) use a hydrocarbon stapled peptide of the exact same sequence identity (SEQ ID NOs: 1-12 of both references), and given that Zhao et al. (381) provide clear motivations to link any residues i and i+7 within 191-205, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the instant application to link any of the eight possible connections with a reasonable expectation of stabilization the α-helical structure.
With regard to claim 2, Zhao et al. (939) disclose that the hydrocarbon stapled peptide contain (R)-2-amino-2-methyl-9-decenoic acid residues and (S)-2-amino-2-methyl-6-heptenoic acid residues (see SEQ ID NOs: 1-12 in the sequence listing of the reference).
With regard to claim 4, Zhao et al. (939) claim a pharmaceutical composition comprising the hydrocarbon-stapled polypeptide discussed above (see claim 2).
With regard to claim 5, as discussed above, Zhao et al. (939) disclose that the hydrocarbon stapled peptide contain (R)-2-amino-2-methyl-9-decenoic acid residues and (S)-2-amino-2-methyl-6-heptenoic acid residues (see SEQ ID NOs: 1-12 in the sequence listing of the reference).
Conclusion
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 SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
