Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment after non-final office action filed May 4, 2026 is acknowledged. Claims 1-4, 10, and 15 were amended and claims 1-16 are pending.
*After further review, a second Non-final follows due to mis-interpretation of the “therapeutic moiety” definition in the specification. A new rejection under 35 U.S.C. 103 follows.
Election/Restrictions
The restriction was deemed proper and made FINAL in the previous office action.
Claims 1-16 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of claims 1-16 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed May 4, 2026.
The rejection of Claim(s) 1, 3, 6, 11, 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qian (ACS Chem. Biol, 2013, 8, 423-431, cited in IDS) is withdrawn in view of amendment of the claims filed May 4, 2026.
The rejection of claim(s) 1-9, 11-14, 16 under 35 U.S.C. 103 as being unpatentable over Qian (ACS, Chem. Biol, 2013, 8, pages 423-431, cited in IDS) in view of Rothbard (J. Med. Chem. 2002, 45, 3612-3618) is withdrawn in view of amendment of the claims filed May 4, 2026 and the fact Applicants pointed out that the therapeutic moiety can be a label but it must have reduce symptoms of a disease or disorder.
The rejection of claim(s) 1-16 under 35 U.S.C. 103 as being unpatentable over Qian (ACS, Chem. Biol, 2013, 8, pages 423-431) in view of Rothbard (J. Med. Chem. 2002, 45, 3612-3618) as applied to claims 1-9, 11-14, 16 above, in further view of Qian* (Biochemistry 2014, 53, 4034−4046) is withdrawn in view of amendment of the claims filed May 4, 2026 and the fact Applicants pointed out that the therapeutic moiety can be a label but it must have reduce symptoms of a disease or disorder.
The rejection of claims 1-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Copending Application No. 19329358 (reference application) in view of Qian* ((Biochemistry 2014, 53, 4034−4046) is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 a on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of Copending Application No. 19329410 (reference application) is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of Copending Application No. 19329427(reference application) is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6, 8, 10, 13-19, 23, 26, 30, 35, 46, 50-53 of Copending Application No. 18278259 (reference application) in view of Qian* and Rothbard (cited above) is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of Copending Application No. 19329353 (reference application) in view of Qian* and Rothbard (cited above) is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of Copending Application No. 19329423 (reference application) in view of Qian* is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
The rejection of claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of Copending Application No. 19329440 (reference application) in view of Qian* is withdrawn in view of the filing and approval of a terminal disclaimer on May 4, 2026.
Terminal Disclaimer
The terminal disclaimers filed on May 4, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of AN19/329410, AN19/329358, AN19329427, AN19/329440, AN19/329423, AN19/329353, 18/278259 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Maintained/Revised Rejections
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 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.
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 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74, 82-83, 88-89 of Copending Application No. 18/688096(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
PNG
media_image1.png
98
521
media_image1.png
Greyscale
wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAz, at each instance, are independently selected from an amino acid; AAU is glutamine and the cargo moiety is conjugated to the side chain of AAu; wherein:two amino acids selected from AA1 AA2, AA3, AA4, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, and AAz are independently a hydrophobic amino acid selected from….. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 18/688096 claims a cyclic peptide attached to a therapeutic moiety via a linker (see claims 74, 83). Copending Application No. 18/688096 claims wherein the CPP has a glutamine as the AAsc (site of attachment, see claim 88); two arginine residues (see claim 83); glycine adjacent to the arginine residues (claim 83), phenylalanine (claim 83) and wherein the linker is PEG2 (minipig) and wherein all amino acids are in L-configuration.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s argument
Applicant argues that “The '096 application does not qualify as a references for purposes of the judicially created obviousness-type double patenting doctrine because (a) the '096 application has a later filing date as compared to the pending application and (b) any patent claim that would issue from the '096 application is expected to expire later than any patent claim that would issue from the pending application (See, e.g., Allergan USA, Inc. V. MSN Labs. Priv. Ltd., 111 F.4th 1358 (Fed. Cir. 2024); see also, Acadia Pharms. Inc. v. Aurobindo Pharma Ltd. No. 2024-1401, 2025 U.S. App. LEXIS 14044 (Fed. Cir. 2025); see also, Ex parte Mates, Appeal No. 2025-001500, PTAB Dec. 23, 2025; see also, Ex parte Chung, Appeal No. 2024-001838, PTAB Feb. 18, 2025; see also, Ex parte Baurin, Appeal No. 2024-002920, PTAB Nov. 11, 2024)¹. The pending application has an earliest non-provisional filing date of November 22, 2017, and an expected expiration date of no later than November 22, 2037. The '096 application on the other hand has a much later earliest non-provisional filing date of August 30, 2022, and an expected expiration date of August 30, 2042. The judicially created doctrine of nonstatutory double patenting "is to prevent patentees from obtaining a second patent on a patentably indistinct invention to effectively extend the life of a first patent to that subject matter." Allergan V. MSN at 1369. And for applications that were filed after the Uruguay Round Agreements Act (URAA) introduced a 20-year patent term from the earliest U.S. filing date "the 'unjustified patent term extension justification for obviousness-type double patenting has limited force" Allergan at 1367 (quoting In re Fallaux, 564 F.3d 1313, 1318 (Fed. Cir. 2009)). Post-URAA the Federal Circuit now focuses their double patenting analysis on the expected expiration date of the rejected patent to prevent an unjustified timewise extension. Following this unjustified timewise extension rationale, the court in Allergan determined that allowing the later-filed child patents at issue to be used as ODP references would be "untenable." Allergan at 1371. In the present case, any claim that would issue from the currently pending application would expire years before any claim that would issue from the later filed '096 application and thus there is no timewise extension. This fact pattern has been addressed in multiple Patent Trial and Appeal Board (PTAB) decisions which have considered Allergan including at least Ex parte Mates, Ex parte Chung, and Ex parte Baurin which each found that a double patenting rejection was defective if there was no unjustified extension of time. For example, on December 22, 2025, the PTAB issued a decision in Ex parte Mates where it found on the basis of the Federal Circuit's Allergan V. MSN decision that a later filed copending reference patent was unavailable for use in a nonstatutory double patenting rejection. In Ex parte Mates, the rejected claims of the Mates application had an earliest non-provisional filing date of April 14, 2013, while the reference copending application that the Examiner used to reject the claims had an earliest non-provisional filing date of March 22, 2019. Based on the fact that any patent claims issuing from the Mates application were not expected to expire after the statutory term of the later-filed reference application, the Board concluded that the copending application could not serve as a reference against the claims of the Mates application and reversed the nonstatutory double patenting rejection. When reversing the OTDP rejection of Mates the panel acknowledged that "exact expiration dates may not be able to be determined for a pending application because PTE and PTA might be awarded", however, "an Examiner can determine the apparent expiration date i.e., 20 years from the earliest effective filing date, shortened by any terminal disclaimers in the file." Mates at 14-15. Thus, the provisional OTDP rejection of Mates was reversed because the Mates application was expected to expire before the copending application. Like in Mates the presently examined application is expected to expire well before the '096 application (November 22, 2037, VS August 30, 2042). Likewise in Ex parte Chung, Appeal No. 2024-001838, PTAB Feb. 13, 2025, the PTAB reversed the provisional nonstatutory double patenting rejection which was based on a later filed copending application. The rejected claims of the Chung application had an earliest non- provisional filing date of December 29, 2017, while the reference copending application that the Examiner used to reject the claims had an earliest non-provisional filing date of July 19, 2018. In the appeal, Appellant argued that the provisional nonstatutory double patenting rejection was in error as the copending reference application was filed after the Chung application and that the claims of the Chung application were otherwise in condition for allowance. The Board agreed with Appellant and reversed the rejection. When making this decision, the Board concluded that the nonstatutory double patenting rejection did not apply to the appealed case and cited Allergan USA, Inc V. MSN Labs. Private Ltd. The fact pattern in the present case is similar to the fact pattern of Ex parte Chung. The present application has an earlier filing date as compared to the alleged reference '096 application which is expected to expire years after the present application's expiration. The decision of the Federal Circuit in Allergan V. MSN as applied by the PTAB indicates that a later filed and later expiring reference application is unavailable for purposes of a nonstatutory double patenting rejection. The '096 application is both later filed and has a later expected expiration than the present application. Applicant respectfully requests the withdrawal of this rejection.
Response to Applicant’s Arguments
Applicants arguments have been fully considered but not found persuasive. Applicant argues that copending Application No. 18/688,096 cannot properly serve as the basis for a provisional nonstatutory double patenting rejection because the ’096 application has a later earliest non-provisional filing date and a later projected expiration date than the presently pending application. Applicant further relies upon Allergan USA, Inc. v. MSN Labs. Priv. Ltd., 111 F.4th 1358 (Fed. Cir. 2024), and several nonprecedential PTAB decisions.
However, Applicant’s arguments do not address the full scope and purpose of the doctrine of nonstatutory obviousness-type double patenting as set forth in the MPEP and Federal Circuit precedent. As explained in MPEP §804, the doctrine is a judicially created doctrine grounded in public policy that is intended not only to prevent unjustified timewise extension of patent rights, but also to prevent the potential harassment of the public by multiple assignees asserting patentably indistinct claims. See also In re Van Ornum, 686 F.2d 937, 944-45 (CCPA 1982).
Further, 37 CFR 1.321(c)(3) expressly requires that a terminal disclaimer filed to overcome a nonstatutory double patenting rejection include a provision that any patent granted on the application shall be enforceable only during such period that it and the reference patent are commonly owned. Thus, the regulatory framework governing terminal disclaimers confirms that common ownership concerns remain an independent and recognized basis underlying nonstatutory double patenting practice.
Applicant’s reliance on projected expiration dates is also not persuasive. As noted in MPEP §1701, Office personnel may not issue binding determinations regarding the expiration date of any patent. Moreover, patent term calculations may ultimately be affected by patent term adjustment, patent term extension, disclaimers, or other post-prosecution events. Accordingly, the Office continues to apply nonstatutory double patenting analysis based upon the claims presented and the governing guidance set forth in MPEP §§804-804.03.
Applicant’s reliance upon Allergan is acknowledged but not controlling under the present facts. Allergan addressed a specific factual scenario concerning whether a later-filed, later-expiring patent could create an improper timewise extension of patent rights. However, Allergan did not eliminate the longstanding policy concern regarding multiple assignees asserting patentably indistinct claims, nor did it overrule MPEP §804 or the requirements of 37 CFR 1.321(c).
Applicant additionally cites nonprecedential PTAB decisions including Ex parte Chung, Ex parte Mates, and Ex parte Baurin. However, nonprecedential PTAB decisions are not binding authority on the Examiner. Furthermore, as noted in prior Office responses in related matters, at least some cited PTAB proceedings involved pending rehearing requests or fact-specific procedural circumstances not controlling here. The present rejection is provisional because the cited application remains pending. The claims of the present application are not patentably distinct from the claims of copending Application No. 18/688,096 for the reasons previously set forth in the rejection. The provisional rejection properly preserves the Office’s ability to address potential issuance of multiple patents claiming patentably indistinct subject matter. Accordingly, Applicant’s arguments have been fully considered but are not persuasive, and the provisional nonstatutory double patenting rejection is maintained.
Claims 1-16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 11168310 in view of Qian (2014, see above) and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
PNG
media_image1.png
98
521
media_image1.png
Greyscale
wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAz, at each instance, are independently selected from an amino acid; AAU is glutamine and the cargo moiety is conjugated to the side chain of AAu; wherein:two amino acids selected from AA1 AA2, AA3, AA4, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, and AAz are independently a hydrophobic amino acid selected from….. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
US Patent No. 11168310 B claims a cyclic peptide comprising instant formula IIIB conjugated via a linker to a therapeutic agent (see claim 1). US Patent No. 11168310 B claims wherein the CPP comprises amino acids 14-101, 108, 110, 124-127 which comprises sequences that falling within instant claims 1-14 and 16 (two arginine, glutamine, phenylalanine). US Patent No. 11168310 B further claims the complex comprising PEG (see claim 32).
US Patent No. 11168310 is silent to wherein the peptides comprising a glycine or two glycines. However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of US Patent No. 11168310 (for example SEQ ID NO:32-35. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of US Patent. No. ‘310 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
US Patent No. 11168310 is silent to specifically miniPEG
However, Qian teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of US Patent. No. ‘310 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian. Qian teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of US Patent. No. ‘310 with the miniPEG linker of Qian as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian demonstrates that miniPEG-linked CPP conjugates remain functional.
Response to Applicant’s Arguments
Neither the claims nor the specification of the reference patent teach or suggest a cyclic peptide with a cargo comprising a linker, a therapeutic moiety, and a targeting moiety.
The claims of the '310 Patent describe linking a cyclic cell penetrating peptide to an enzyme, thymidine phosphorylase. The claims are silent with respect to any targeting moiety or even that there might be a need for a targeting moiety. As mentioned by the Examiner, the '310 Patent is also silent as to peptides comprising one or more glycine residues. This deficiency is not remedied by either Rothbard alone or in combination with Qian*.
As described above, Rothbard teaches a series of linear (not cyclic) peptides comprising 6- 10 arginines and 6-10 spacer groups. Rothbard et al. teaches the significant uptake enhancement of including 6-aminocaproic acid into linear arginine rich peptides. To the extent that Rothbard is instructive to the skilled artisan at all regarding cyclic peptides, the teaching is that 6-aminocaproic acid is by far the best spacer, not glycine. Rothbard teaches away from the use of glycine (an a- amino acid) in the discussion, where the authors conclude that: "The rate of uptake increased as the number of methylenes in the non-a-amino acids increased" (Second to last paragraph on page 3616, emphasis added).
With respect to Qian, the Applicant respectfully points out that each of compounds 8-12 have a cargo consisting solely of phosphocoumaryl aminopropionic acid ("pCAP"). pCAP is a detectable moiety, not a therapeutic moiety or targeting moiety. Qian does not teach or suggest the combination of miniPEG as a linker with either a therapeutic moiety or a targeting moiety. Qian certainly does not teach the use of a miniPEG linker with a cargo comprising both a therapeutic moiety and a targeting moiety.
The Applicant would like to respectfully point out that none of (i) U.S. Patent No. 11,168,310; (ii) Rothbard; or (iii) Qian teach or suggest the cargo of pending claim 1, i.e. a cargo moiety comprising a therapeutic moiety and a targeting moiety. Nor do the references teach the inclusion of glycine as a hydrophobic amino acid (indeed Rothbard teaches away from the use of glycine). The references alone or in combination do not teach the compounds of claims 1-16. Applicant respectfully requests the withdrawal of this rejection.
Applicants arguments have been fully considered but not found persuasive. As set forth in the rejection, the nonstatutory double patenting rejection is based primarily on the claims of the ‘310 patent, which claim cyclic peptide conjugates encompassing the presently claimed cyclic peptide framework. Rothbard and Qian are relied upon only to demonstrate that the additional claimed limitations, including glycine spacing residues and miniPEG linkers, would have been obvious modifications of the cyclic peptide conjugates recited in the ‘310 patent. A nonstatutory double patenting rejection may properly rely on secondary references to demonstrate that differences between the claims constitute obvious variations (see MPEP 804). Applicant’s argument that the ‘310 patent does not expressly recite a targeting moiety is not persuasive because the claims of the instant application broadly recite a cargo moiety “comprising” a linker moiety, therapeutic moiety, and targeting moiety. The transitional term “comprising” is open ended. THe ‘310 patent teaches conjugation of therapeutic cargo to cyclic CPP constructs, and Qian teaches additional linker architectures and conjugation strategies suitable for cyclic CPP cargo delivery systems. Selection or incorporation of additional targeting functionality into known CPP therapeutic conjugates would have constituted no more than the predictable use of known targeting technologies in the art to improve delivery specificity.
Applicant’s argument that Qian discloses only detectable moieties is similarly not persuasive. Qian expressly teaches cyclic CPP conjugates linked to cargo moieties through miniPEG linkers and demonstrates that such linker systems maintain functionality and uptake properties. One of ordinary skill in the art would have recognized that the linker strategy disclosed in Qian is not limited solely to fluorescent or detectable cargos, but is generally applicable to conjugated cargo delivery systems, including therapeutic and targeting moieties.
Applicant further argues that Rothbard teaches away from glycine because longer non-α-amino acid spacers, particularly 6-aminocaproic acid, exhibited greater uptake enhancement. However, Rothbard does not criticize, discredit, or otherwise discourage the use of glycine residues. Rather, Rothbard expressly teaches that incorporation of glycine residues into arginine-rich peptides increases spacing between arginine residues, enhances backbone flexibility, and improves cellular uptake relative to unsubstituted controls. The fact that Rothbard identifies certain alternative spacers as providing still greater uptake enhancement does not constitute a teaching away from glycine. A reference does not teach away merely because it discloses that one embodiment may be superior to another.
Moreover, Rothbard consistently teaches the general principle that increasing conformational flexibility and spacing between arginine residues enhances uptake properties. Glycine was expressly identified as one suitable spacer within that broader teaching. Thus, one of ordinary skill in the art would have had reason to incorporate glycine residues into the cyclic peptide conjugates of the ’310 patent to obtain the predictable benefit of modulating arginine spacing and peptide flexibility while maintaining CPP functionality.
Applicant additionally argues that Rothbard concerns linear rather than cyclic peptides. However, the Examiner notes that Rothbard is relied upon for its teachings regarding the functional effects of amino acid spacing, methylene insertion, conformational flexibility, and uptake enhancement in arginine-rich CPP systems. The applicability of these teachings is not limited solely to linear peptides. One of ordinary skill in the art would reasonably have expected such spacing and flexibility principles to apply to cyclic CPP constructs as well, particularly where the cyclic peptides of the ’310 patent likewise rely upon arginine-rich uptake functionality.
With respect to the claimed placement of glycine residues adjacent to arginine residues, the Examiner maintains that selection of residue number and placement represents routine optimization of recognized result-effective variables, namely arginine spacing, backbone flexibility, and uptake enhancement. Rothbard expressly teaches that uptake properties correlate with spacing modifications between arginine residues. Optimization of the location and number of glycine spacers to achieve desired uptake characteristics would therefore have been within the ordinary skill in the art.
Accordingly, the Examiner maintains that the combined teachings of the ’310 patent, Rothbard, and Qian render the presently claimed subject matter an obvious variation of the patented claims. Applicants’ arguments have been fully considered but are not persuasive. Therefore, the rejection is maintained.
Claims 1-16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10626147 in view of Qian (2014) and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
PNG
media_image1.png
98
521
media_image1.png
Greyscale
wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAz, at each instance, are independently selected from an amino acid; AAU is glutamine and the cargo moiety is conjugated to the side chain of AAu; wherein:two amino acids selected from AA1 AA2, AA3, AA4, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, and AAz are independently a hydrophobic amino acid selected from….. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
US Patent No. 10626147 B claims a cyclic peptide comprising instant formula II-A-IIC conjugated via a linker to a cargo (see claim 7). US Patent No. 106226147 B claims a cyclic peptide comprising at least two arginine residues, hydrophobic amino acids including phenylalanine, wherein m and p are 1, m is 0 (resulting in an 8mer) with a terminal glutamine and wherein the cargo is attached to the glutamine. US Patent No. 106226147 further claims having all L-amino acids (claim 5) and the cargo comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof (claim 6).
US Patent No. 10626147 is silent to wherein the peptides comprising a glycine or two glycines. However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of US Patent No. 10626147. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of US Patent. No. ‘147 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
US Patent No. 10626147 is silent to specifically miniPEG
However, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of US Patent. No. ‘147 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linking of the cargo moiety of US Patent. No. ‘147 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Response to Applicant’s Arguments
Applicant argues “The present claims are limited to a compound comprising a cyclic peptide wherein "two amino acids selected from AAi, AA2, AA3, AA4, and AAz are arginine with the remaining amino acids being an amino acid other than arginine" (Claim 1, emphasis added). In contrast, claims 1-21 of the '147 Patent exclusively describe compounds with 3-5 arginine residues. The skilled artisan reading the claims of the '147 Patent would not expect that a cyclic peptide with fewer than 3 arginine residues would work, especially given the vast majority of the claims are directed to compounds with 4 or 5 arginine residues. This deficiency is not remedied by Rothbard or Qian (2014). In fact, both Rothbard and Qian further confirm to the skilled artisan that four or more arginine residues are required for sufficient uptake. Rothbard confirms this teaching. Rothbard describes the uptake of compounds with six or more arginine residues. Their model system was a 10-amino acid peptide with seven arginine residues. On page 361, Rothbard et al describe how inclusion of aspartic acid or glutamic acid at positions 2, 5, and 8 of the peptide results in "relatively poor" cell uptake. This effect is attributed to salt bridges between the arginines and the carboxylate side chain of the aspartic or glutamic acids at 2, 5, and/or 8.
"These mixed decapeptides exhibited a wide range of abilities to enter the cells due to their differing amino acid substitution at positions 2, 5, and 8. Decapeptides with aspartic and glutamic acids at these positions entered cells relatively poorly. This is in agreement with previous experiments indicating that the guanidine headgroup of arginine can form intramolecular salt bridges with either phosphate or carboxylate functionalities, and in so doing reduce the number of guanidines available for transport (unpublished results)" (Rothbard, p.3614, right column last paragraph, emphasis added)
The results taught by Rothbard is consistent with the claims of the '147 Patent. Rothbard teaches that "relatively poor" uptake would be expected for a peptide with four or fewer arginines2.. The skilled artisan would not ignore the teaching of two different references that consistently suggest the same limitation - both references teach that four or more arginine residues results in superior cellular uptake.
The teaching of Qian* with respect to number of arginine residues is consistent with both '147 Patent as well as Rothbard - four or more arginine residues result in cellular uptake. None of the compounds in Qian* have less than three arginines.
For example, Figure S1 shows six exemplary compounds used in the publication. These compounds consistently have four arginines in the cyclic peptide (figure reproduced on next page, arginine residues circled). One of the compounds has four arginines in the cyclic peptide with an additional five exocyclic arginines.
The one compound in Qian that has less than four arginine residues is Antp (compound 22), which has three. Qian et al. made a conjugate of Antp, called "Antp-PCP" (Compound 12). As described above, Compound 12 (treatment group VI; 400 AU of MFI) was found to be nearly an order of magnitude worse than cFCDR4-PCP (treatment group II; 3510 AU of MFI). The skilled artisan would not be motivated to select a compound that is demonstrably worse by almost an order of magnitude. Instead, the skilled artisan would consider the cyclic peptide of treatmentgroup II, which has four arginines All three of the references provide the skilled artisan a consistent teaching that four or more arginines are advantageous for cell uptake. The skilled artisan would not ignore three different references teaching the same limitation.
With respect to glycine, as described above, Rothbard teaches a series of linear (not cyclic) peptides comprising 6-10 arginines and 6-10 spacer groups. Rothbard et al. teaches the significant uptake enhancement of including 6-aminocaproic acid into linear arginine rich peptides. To the extent that Rothbard is instructive to the skilled artisan at all regarding cyclic peptides, the teaching is that 6-aminocaproic acid is by far the best spacer, not glycine. Rothbard teaches away from the use of glycine (an a-amino acid) in the discussion, where the authors conclude that: "The rate of uptake increased as the number of methylenes in the non-a-amino acids increased" (Second to last paragraph on page 3616, emphasis added).
With respect to the miniPEG linkers of Qian, the Applicant respectfully points out that each of compounds 8-12 have a cargo consisting solely of phosphocoumaryl aminopropionic acid ("pCAP"). pCAP is a detectable moiety, not a therapeutic moiety or targeting moiety. Qian does not teach or suggest the combination of miniPEG as a linker with either a therapeutic moiety or a targeting moiety. Qian* certainly does not teach the use of a miniPEG linker with a cargo comprising both a therapeutic moiety and a targeting moiety.
Applicant’s arguments have been fully considered but not found persuasive. As an initial matter, the nonstatutory double patenting rejection is based on the claims of the ’147 patent, which disclose cyclic peptide cargo conjugates encompassing the same general inventive concept as presently claimed. Rothbard and Qian are relied upon only for evidence that the presently recited glycine substitutions and miniPEG linker limitations would have been obvious modifications of the compounds recited in the ’147 patent. A nonstatutory obviousness-type double patenting rejection may properly rely upon secondary references to demonstrate that differences between the claims would have been obvious to one of ordinary skill in the art. See MPEP §804.
Applicant’s argument that the prior art teaches away from peptides containing fewer than four arginine residues is not persuasive. The claims of the ’147 patent are not limited exclusively to compounds containing four or more arginine residues. Rather, the claims broadly encompass cyclic CPP constructs containing arginine residues and hydrophobic amino acids conjugated to cargo moieties. Although certain embodiments within the references may demonstrate improved uptake with increased arginine content, disclosure of preferred embodiments does not amount to a teaching away from less preferred embodiments.
Moreover, Applicant’s arguments improperly attack the references individually rather than the combined teachings of the references as relied upon in the rejection. The issue is not whether Rothbard or Qian individually disclose the exact claimed peptide, but whether the combined teachings would have suggested the presently claimed modifications to one of ordinary skill in the art.
Rothbard expressly teaches that incorporation of glycine residues into arginine-rich CPPs increases spacing between arginine residues, enhances conformational flexibility, and improves cellular uptake. Rothbard specifically attributes improved uptake to increased spacing and backbone flexibility produced by insertion of methylene-containing spacers, including glycine residues. Thus, Rothbard provides affirmative guidance that modulation of arginine spacing constitutes a recognized result-effective variable affecting uptake properties.
Applicant’s argument that Rothbard “teaches away” from glycine because 6-aminocaproic acid exhibited greater uptake enhancement is not persuasive. A reference does not teach away merely because it discloses that one embodiment may provide superior performance relative to another. Rothbard nowhere criticizes, discredits, or discourages the use of glycine spacers. Rothbard expressly reports that glycine incorporation improved uptake relative to unsubstituted peptides. The disclosure that certain longer spacers may provide additional enhancement merely reflects optimization among known alternatives and does not negate Rothbard’s positive teaching regarding glycine.
Applicant additionally argues that Rothbard concerns linear peptides rather than cyclic peptides. However, Rothbard is relied upon for its teachings regarding arginine spacing, conformational flexibility, and uptake behavior in CPP systems generally. One of ordinary skill in the art would reasonably have expected these physicochemical principles to apply to cyclic CPP constructs as well, particularly where both Rothbard and the ’147 patent concern arginine-rich cell penetrating peptides intended for intracellular delivery.
Applicant further argues that Qian fails to teach miniPEG linkers in conjunction with therapeutic or targeting moieties because compounds 8-12 allegedly employ only detectable moieties. The Examiner disagrees. Qian expressly teaches miniPEG (8-amino-3,6-dioxaoctanoic acid) as a suitable linker for conjugating cargo moieties to cyclic CPP constructs while maintaining uptake functionality. The relevance of Qian is not limited to the precise identity of the cargo moiety exemplified. One of ordinary skill in the art would have understood that the disclosed miniPEG linker architecture is broadly applicable to conjugated CPP cargo systems, including therapeutic and targeting moieties (Table 1 of Qian), because linker selection is generally independent of the biological identity of the attached cargo. Furthermore, the ’147 patent itself expressly contemplates cargo moieties comprising detectable moieties, therapeutic moieties, targeting moieties, or combinations thereof. Thus, combining the linker teachings of Qian with the cargo conjugate teachings of the ’147 patent would have represented no more than the predictable use of known linker technology in an analogous delivery system. Substitution of one known linker for another to obtain predictable spacing and delivery properties constitutes an obvious design choice. See MPEP2143.
Applicant’s arguments regarding allegedly inferior uptake of certain Qian constructs containing fewer arginine residues are likewise not persuasive (this is further evidenced by Qian* (2016, see above rejection). Differences in degree of uptake among embodiments do not establish that lower arginine constructs were inoperative or unsuitable for CPP function. Rather, the references collectively demonstrate that uptake properties may be modulated through optimization of residue composition, spacing, flexibility, and linker selection. Such optimization of recognized result-effective variables would have been within the ordinary level of skill in the art. Accordingly, the Examiner maintains that the presently claimed compounds represent obvious variations of the compounds recited in the ’147 patent in view of the teachings of Rothbard and Qian. Therefore, the rejection is maintained.
New Rejections
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.
Claim(s) 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Qian (J Biochemistry 2014, 53, 4034−4046, 2014, cited previously) in view of Qian* ( Biochemistry 2016, 55, 2601−2612, cited in Applicant’s IDS), Rothbard (J. Med. Chem. 2002, 45, 3612-3618, cited previously) and Pei (WO2015179691, cited in Applicant’s IDS).
Claim interpretation: Because the claimed peptides are cyclic, the peptide does not possess a fixed N-terminus or C-terminus in the same manner as a linear peptide. Rather, the amino acid residues form a continuous ring structure in which sequence orientation is arbitrary absent an express structural limitation requiring a particular residue to occupy a terminal position. Accordingly, the recited glutamine residue (AAu) is not limited to an N-terminal or C-terminal position, and cyclic peptide structures disclosed in the prior art containing glutamine residues conjugated to cargo satisfy the claimed glutamine limitation regardless of the point selected as the starting position for depicting the cyclic sequence.
Qian teaches cyclic cell penetrating peptides (CPPs) useful for intracellular delivery of attached cargo molecules into mammalian cells. Qian teaches cyclic peptides comprising arginine residues, hydrophobic residues including phenylalanine and napthylalanine (Φ) and glutamine residues used for cargo attachment (see Abstract, Figure 1, Table 1). Qian further teaches exocyclic attachment of cargo to the glutamine side chain and delivery of therapeutic cargoes including dexamethasone (“Dex”), including peptide 2, cyclo(FΦRRRRQ)K(Dex)-NH2 (see figure 1B, Table 1). Accordingly, Qian teaches a cyclic peptide, a cargo moiety conjugated to the peptide through glutamine, a linker moiety (lysine linker between peptide and cargo, which Qian also teaches minipeg as a spacer and/or linker); a therapeutic moiety (Dex), hydrophobic amino acid residues including Phe and Φ and a targeting moiety. With respect to the targeting moiety, Applicant’s specification states the targeting moiety may overlap with or comprise parts of the CPP itself (see spec 0210). Qian teaches that the disclosed cyclic CPPs mediate cellular uptake, endosomal escape and intracellular delivery of the attached cargoes into mammalian cells (see Abstract, Figures 1-2). Therefore the cyclic CPPs of Qian constitute the claimed targeting moiety under the broadest reasonable interpretation consistent with Applicant’s specification.
Qian differs from the presently claimed invention in that the exemplified peptides contain four arginine residues rather than two arginine residues as presently claimed.
However, Qian* teaches that intracellular delivery efficiency and cellular uptake properties of cyclic CPPs depend on the number and arrangement of arginine and hydrophobic residues within the cyclic peptide scaffold (see e.g. abstract, Table 1, figures 2-5). Qian* further teaches cyclic CPP variants having reduced arginine content while maintaining uptake activity comparable to higher arginine analogues, thereby demonstrating that arginine content and arrangement were a recognized result effective variable subject to optimization.
Rothbard introduces glycine residue into a polyarginine CPP (see abstract). Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to modify the cyclic CPPs of Qian in view of the optimization teachings of Qian* and the arginine spacing teachings of Rothbard by reducing arginine content and replacing one or more arginine residues with non-arginine residues, including glycine residues. One of ordinary skill in the art would have been motivated to do so to increase spacing between remaining arginine residues, optimize peptide flexibility, optimize intracellular uptake and endosomal escape properties and maintain effective intracellular cargo delivery. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Qian* expressly teaches that cyclic CPPs having reduced arginine content retain uptake properties comparable to higher arginine analogs, thereby providing a reasonable expectation that further optimization of arginine number and spacing would preserve delivery functionality. Rothbard further teaches that spacing arginine residues with non arginine residues such as glycine predictably improves CPP uptake behavior and flexibility. Because residue composition and residue spacing were recognized result effective variables in cyclic CPP systems, such modification would have constituted routine optimization yielding predictable results (see MPEP 2143). Such modifications would have predictably resulted in cyclic CPP embodiments containing fewer arginine residues, including embodiments containing two arginine residues separated by non arginine residues and at least two hydrophobic residues as presently claimed. Exemplary resulting modified peptides would include cyclic peptides having arrangements such as cyclo(FΦGRGRQ)-Lys-linked therapeutic cargo constructs OR cyclo(FΦRGRGQ)-Lys , which retain the cyclic CPP scaffold, glutamine linked cargo conjugation, hydrophobic residues, therapeutic cargo delivery functionality and cellular targeting delivery properties taught by Qian.
Regarding claim 2, Rothbard expressly teaches glycine containing arginine spaced CPPs and the combination of Qian in view of Qian* and Rothbard render obvious the peptide cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys.
Regarding claim 3, Qian teaches wherein at least one amino acid is a Phe (see Table 1) and the combination of Qian in view of Qian* and Rothbard render obvious the peptide cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys.
Regarding claim 4 and 5,The combination of Qian in view of Qian* and Rothbard render obvious obvious the peptide cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys which comprises glycine and phenylalanine.
Regarding claims 6-8, The combination of Qian in view of Qian* and Rothbard render obvious the obvious the peptides cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys which comprises arginine adjacent to a hydrophobic amino acid residue (glycine and or Φ) and wherein both arginine residues are adjacent to a glycine).
Regarding claims 9 and 14, 16, Qian and Qian* teaches that all of the amino acids are in the natural stereo configuration (“L amino acid”) thus meeting the limitations of instant claims 9 and 16 (see peptides in Table 1 of both references, for example peptides 8,19 of Qian and peptide 1,4 of Qian*.
Regarding claims 11-13, The combination of Qian in view of Qian* and Rothbard render obvious the peptides cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys which comprises arginine adjacent to a hydrophobic amino acid residue (glycine and or Φ) and wherein both arginine residues are adjacent to a glycine).
With arginine substitutions, Qian in view Qian* teaches the peptide cyclo(FΦRRRRQ), if an arginine residue is substituted with glycine to separate out the arginine residues the resulting peptide would be cyclo(FΦRGRGQ)-Lys or cyclo(FΦGRGRQ)-Lys. Inserting the glycine at this position would result in the greatest separation of the arginine residues. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
Regarding claims 10 and 15, Qian teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
Regarding claims 10 and 15, It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Qian in view of Qian* and Rothbard to include additionally miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian. Qian teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of Qian with the miniPEG linker of Qian as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian demonstrates that miniPEG-linked CPP conjugates remain functional and cargo attachment to the side chain of glutamine. Furthermore, it would have been obvious to one of ordinary skill in the art to use both lysine mediated conjugation and a miniPEG linker because lysine provides a conjugation site while miniPEG provides spacing and flexibility between the CPP and cargo. Combining these known elements for their established functions would have yielded predictable results.
Additionally, even assuming arguendo that the claims require a targeting moiety separate from the CPP itself (which the current claims do not require based on Applicants definition in the specification), Pei expressly teaches incorporating targeting moieties into the cargo portion of CPP constructs (see claims 12, 40, abstract). Pei discloses that a cargo moiety may comprise a targeting moiety and further teaches targeting sequences capable of binding enzyme domains or inhibiting disease-related proteins such as Ras, PTP1B, Pin1, Grb2 SH2, and CAL PDZ (claims 47, 51, 58 etc..).
One of ordinary skill in the art would have been motivated to incorporate the targeting moieties taught by Pei into the cyclic CPP delivery systems of Qian in view of Qian* and Rothbard in order to provide selective intracellular targeting of disease related proteins and improve therapeutic specificity. Pei expressly teaches that targeting moieties may comprise amino acid sequences capable of binding enzyme domains or inhibiting disease related proteins including Ras, PTP1B, Pin1, Grb2 SH2 and CAL PDZ. Because Qian already teaches efficient cellular intracellular and cytosolic delivery of therapeutic cargoes through glutamine side chain conjugation a person of ordinary skill in the art would have recognized that incorporating Pei’s targeting moieties into Qian’s CPP constructs would predictably improve localization and targeting of the delivered therapeutic cargoes while retaining cellular uptake properties of the cyclic CPP structure.
Accordingly, modifying Qian’s in view of Qian* and Rothbards cyclic CPP constructs to additionally include a targeting moiety as taught by Pei would have represented the predictable use of prior art elements according to their established functions.
Response to Applicant’s Arguments
*Please note that Majority of Applicant’s arguments are moot in light of withdrawal of the previous rejection and the new rejection presented above. However, so Arguments are still relevant and are presented below. Applicants argue that “The Examiner's interpretation that the cyclic peptide itself constitutes a targeting moiety is also an unreasonably broad construction that conflates distinct claim limitations. Claim 1 requires "a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety"-three separate components within the cargo moiety. The specification provides specific examples of targeting moieties in Table 6, which include sequences that can target enzyme domains and can comprise inhibitors against enzymes that play a role in diseases such as cancer, cystic fibrosis, diabetes, or obesity. Qian does not disclose any such targeting moiety as part of the cargo. The Examiner's interpretation that the cyclic peptide of Formula III-B is also the targeting moiety attached to the compound of Formula III-B results in circular logic in claim limitations. This interpretation would render the claim limitation requiring a targeting moiety within the cargo moiety meaningless, as any cell-penetrating peptide would automatically satisfy this requirement simply by virtue of being a cell-penetrating peptide. This interpretation fails to give meaning to the distinct claim requirement that the cargo moiety itself comprises a targeting moiety. Accordingly, Qian does not anticipate a cell-penetrating peptide comprising "a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety" as recited by claim 1. Claims 3, 6, 11, and 16, which depend from claim 1, are allowable for the same reasons. Applicant respectfully requests withdrawal of the rejection.
Applicants arguments have been fully considered but not found persuasive. Claim 1 recites “a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety,” but does not require that the targeting moiety be structurally distinct from, or external to, the cyclic cell-penetrating peptide sequence. Nor does claim 1 require that the targeting moiety comprise a separate targeting ligand or targeting peptide appended to the CPP. The claim merely requires the presence of a targeting moiety within the overall construct.
Applicant’s own specification expressly states that “the targeting moiety and cell penetrating peptide moiety can overlap” and that “the residues that form the cell penetrating peptide moiety can also be part of the sequence that forms the targeting moiety, and vice versa” (Spec. ¶0210). Thus, under the broadest reasonable interpretation consistent with the specification, residues of the CPP itself may constitute or overlap with the claimed targeting moiety.
Accordingly, the Examiner’s interpretation does not “conflate” claim limitations, but instead follows the explicit teachings of Applicant’s specification. The specification expressly permits the same residues to satisfy both the CPP and targeting-moiety limitations.
Qian teaches cyclic arginine-rich/hydrophobic CPPs that bind cellular membranes, mediate cellular uptake, and deliver cargo intracellularly. See, e.g., Qian (2014) Abstract; Qian (2016) Abstract and Table 1. Because Qian’s CPP sequences selectively interact with and target cellular membranes to promote intracellular uptake and delivery, the CPP sequence functions as a targeting element for delivery to cells. Under Applicant’s own definition permitting overlap between the CPP and targeting moiety, Qian therefore teaches or at least suggests the claimed targeting moiety limitation.
Applicant’s argument that the claim requires three structurally separate cargo components is not commensurate with the claim language or specification. While the specification provides examples of distinct targeting moieties, the claims are not limited to those embodiments. It is well established that limitations from preferred embodiments may not be imported into the claims. Here, neither claim 1 nor the specification requires the targeting moiety to be a separate peptide sequence or separate molecular structure from the CPP.
Further, Applicant’s argument that the Examiner’s interpretation would render the limitation meaningless is not persuasive because the claim still requires functionality associated with targeting, which Qian’s CPPs possess. The fact that a single structure may satisfy multiple claim limitations does not render the claim indefinite or meaningless where, as here, the specification expressly permits overlapping functionality. Even assuming arguendo that claim 1 requires a separate targeting moiety distinct from CPP itself, it would have been obvious to include an additional targeting moiety in Qian’s cyclic CPP delivery systems to improve delivery to desired cell/tissues.
Applicant argues “Rothbard does not cure the deficiencies of Qian. Rothbard does not teach or suggest a cyclic peptide comprising a linker moiety, therapeutic moiety, and a targeting moiety. Rothbard describes a series of linear peptides and a study to improve the cellular uptake. The discovery that Rothbard describes is that 6-aminocaproic acid is an excellent spacer in a polyarginine linear peptide, which is not relevant to the presently claimed invention. In fact, 6-aminocaproic acid is several times more potent than the related glycine-containing linear peptide. The skilled artisan reading Rothbard would not select glycine as a spacer when it was consistently outperformed by 6-aminocaproic acid. Instead, the skilled artisan would want to maximize the uptake of its linear peptide and include a 6-aminocaproic acid spacer. Rothbard et al performed a study using the deca-arginine homopolymer R10 and added spacers of different lengths. They describe the uptake of the peptide drastically increasing with increasing number of methylene groups in the spacer: "The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and the carboxyl groups, 4-aminobutyric acid has three, and 6-aminocaproic acid has five. As the number of methylenes increased from one to three to five, the uptake relative to R 7 increased by factors of four, five, and 16, respectively. The peptide with aminocaproic acid spacing entered cells more effectively than RIO" (Rothbard p. 3615, emphasis added).
The skilled artisan reading Rothbard would see that 6-aminocaproic acid (five methylenes) was four times better than glvcine (16-fold vs 4-fold improvement in uptake). Rothbard et al. further studied a series of 12-residue peptides with a (Spacer-Arginine)₆ motif. The spacers used were glycine (CH₂ = 1), ß-alanine (CH₂ = 2), 4-aminobutyric acid (CH₂ = 3), 6-amino caproic acid (CH₂ = 5), or 8-aminocaprylic acid (CH₂ = 7). The trend discovered by Rothbard was a strong increase in uptake with increased methylene count. 6-aminocaproic acid was more than twice as active than glycine in this study. The results are presented in Figure 5, reproduced for reference below, annotated to clearly show the methylene count. The Examiner specifically points to the second to last paragraph on page 3616, reproduced for reference below. However, this paragraph does not teach the skilled artisan to incorporate glycine into a cyclic cell penetrating peptide. This paragraph teaches that the rate of uptake for the series of linear peptides studied by Rothbard was correlated with the non-α-amino acid (e.g. not glycine) content of the linear peptide: "Significantly, with the exception of the analogues containing substitutions with aspartic and glutamic acid, all of the decamers containing seven arginines were more efficient in uptake than heptaarginine itself. These data indicate that independent of the characteristics of the side chain, an increase in spacing between the arginine residues also leads to an increase in cellular uptake. This improved performance was further enhanced when non-a-amino acids were substituted into the 2nd, 5th, and 8th positions. The rate of uptake increased as the number of methylenes in the non-a-amino acids increased. (Second to last paragraph on page 3616, emphasis added). The Examiner characterizes a quote from Rothbard as the author's conclusion that increased methylene units were shown to increase uptake (and therefore the skilled artisan would expect glycine would improve uptake). However, the quote cited by the Examiner is incomplete. Consistent with the citation above, the entire paragraph from Rothbard specifically teaches that the authors themselves believe that non-α-amino acids (e.g. not glycine) were important for enhanced uptake: "The enhanced uptake when non-a-amino acids were substituted into the peptide backbone was very similar to the effect observed when the side chains were extended in the peptoid series. By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake" (Rothbard p. 3617, left column; emphasis added and internal citation omitted; underlined passage cited in the Non-Final Office Action). Rothbard et al. teaches the significant uptake enhancement of including 6-aminocaproic acid into linear arginine rich peptides. To the extent that Rothbard is instructive to the skilled artisan at all regarding cyclic peptides, the teaching is that 6-aminocaproic acid is by far the best spacer, not glycine. Applicant respectfully requests the withdrawal of this rejection.
Applicant’s argument is fully considered but not found persuasive. Applicants arguments regarding 6-amino caproic acid are not persuasive. The rejection does not rely on Rothbard as teaching that glycine was the optimal spacer reside or most effective uptake enhancer among all disclosed spacing groups. Rather, Rothbard is relied upon for teaching that increasing spacing and flexibility between arginine residues affects and predictably modulates cellular uptake properties, thereby demonstrating that residue spacing constituted a recognized result effective variable subject to routine optimization.
Rothbard expressly teaches that incorporation of glycine and other non-arginine residues between arginine residues alters uptake behavior and increases conformational flexibility of the peptide backbone. Although Rothbard reports that longer methylene containing spacers may produce greater uptake enhancement in certain linear peptide systems, Rothbard nevertheless teaches that glycine containing constructs exhibited improved uptake relative to unsubstituted arginine controls and confirms the general principle that modifying spacing between arginine residues predictable affects cellular uptake.
The rejection further relies on Qian* for teaching that cyclic CPPs having reduced arginine content retain uptake functionality, thereby providing additional motivation and reasonable expectation of success for modifying residues composition and arginine spacing within cyclic CPP systems. The claimed invention does not require maximized uptake or selection of an optimal spacer, and obviousness does not require that the prior art teach the preferred or most effective embodiment.
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 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.
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 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of Copending Application No. 19/329431(reference application) in view of Qian (2014). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
PNG
media_image1.png
98
521
media_image1.png
Greyscale
wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAz, at each instance, are independently selected from an amino acid; AAU is glutamine and the cargo moiety is conjugated to the side chain of AAu; wherein:two amino acids selected from AA1 AA2, AA3, AA4, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, and AAz are independently a hydrophobic amino acid selected from….. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329431 claims a cyclic peptide attached to a therapeutic moiety via a linker (see claims 1). Copending Application No. 19/329431 claims wherein the CPP is 8 or 7 amino acids (see claims 5-9); at least two arginine residues and two hydrophobic residues (claim 14); the same formula of the instant claims (claim 17); D or L amino acids (claim 17), two arginine adjacent to glycines (claims 23, 26-27); Copending Application No. 19/329431 is silent to Gln as the site of conjugation.
However, Qian teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid and attachment at a Gln residue. Specifically, Qian defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Copending Application No. 19/329431 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian. Qian teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of Copending Application No. 19/329431 with the miniPEG linker of Qian as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian demonstrates that miniPEG-linked CPP conjugates remain functional.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
Prosecution Insights