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 to the claims filed after non-final office action on August 19, 2026 is acknowledged. Claim 1 was amended and claims 1-16 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL previously. Claims 1-16 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of 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as being unpatentable over claims 1-21 of U.S. Patent No. 10626147 in view of Qian (2014) and Rothbard (cited above) is withdrawn in view of Applicant’s arguments filed August 19, 2026.
The rejection of claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of Copending Application No. 19/329431(reference application) in view of Qian (2014) ) is withdrawn in view of Applicant’s arguments filed August 19, 2026.
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 remain 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.
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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); and the targeting moiety as part of the exocyclic cargo.
Copending Application No. 18/688096 claims a cyclic peptide attached to a therapeutic moiety via a linker and a targeting peptide (see claims 74, 83) and a therapeutic (AC). 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 Examiner has not provided the motivation to go from the present claims to the claims of the ‘096 application such than obviousness rejection is well founded.
Applicants arguments have been fully considered but not found persuasive. Copending Application No. 18/688096 claims a cyclic peptide attached to a therapeutic/targeting moiety via a linker (see claims 74, 83) which falls within the scope of Formula III-B. 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. Thus the company application contains a cyclic peptide of the exact structure of 3B within the claims and thus the 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 below) and Rothbard (cited below) and Pei (cited below). 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.
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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 motivated 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 and exocyclic targeting moiety.
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.
Furthermore, 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 US Patent No ‘310 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 US Patent No. ‘310 CPP constructs would predictably improve localization and targeting of the delivered therapeutic cargoes while retaining cellular uptake properties of the cyclic CPP structure.
Response to Applicant’s Arguments
Applicant argues that skilled origin would not arrive at the claims CPP compounds which have a cargo comprising A linker therapeutic variety and targeting moiety. None of the references teach use of a targeting moiety as a distinct moiety. The skilled origin would not have an expectation of success of altering the compounds of US Patent No. ‘310.
Applicants arguments have been fully considered but not found persuasive. 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 US Patent No ‘310 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 US Patent No. ‘310 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 US Patent No. ‘310 CPP constructs would predictably improve localization and targeting of the delivered therapeutic cargoes while retaining cellular uptake properties of the cyclic CPP structure.
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 remain 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 arginine’swould 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.
Furthermore, regarding the targeting moiety being separate (based on the claim amendment) from the CPP itself, 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
Applicant’s argue that none of the references teach exactly 2 arginines . Qian’s peptide contains four arginine residues, and Applicants contend that the references therefore fail to teach or suggest two arginine cyclic peptide.
Applicant’s arguments have been fully considered but not found persuasive. The rejection does not rely on Qian as expressly disclosing a cyclic peptide having exactly 2 arginine residues. Rather Qian is relied upon for the cyclic CPP scaffold and associated structural features while Qian* and Rothard evidence that arginine number and arrangement were recognized parameters affecting cellular uptake. Obviousness does not require the prior art to expressly exemplify the precise optimized value ultimately claimed. The question is whether a person of ordinary skill would have had reason to optimize a known parameter and a reasonable expectation of obtaining a useful result. The prior art's recognition that cellular uptake varies as a function of arginine content provides reason to optimize the number of arginine residues (result effective variable) rather than requiring preservation of Qian’s for arginine configuration.
Applicant argues that Qian shows that increasing arginine increases uptake. Applicant contends this would direct the skilled artisan toward additional arginine residues rather than two.
Applicants arguments have been fully considered but not found persuasive. Applicants are arguing teaching away from 2 Arg residues because the prior art teaches 3-5 arginine residues. However evidence that one embodiment or range provides greater uptake does not, without more, establish that the art criticizes discredits or discourages investigation of a lower arginine content (see MPEP 2145). If anything, the observed dependence of uptake upon arginine number further supports that the conclusion that arginine content was recognized as a result effective variable that could be optimized.
Apna argues that Qian identifies 3 Argentine as the minimum and Qian’s statement concerning peptides having as few as 3 arginine residues and argues that a skilled artisan would not have reduced the number further to two.
Applicants arguments have been fully considered but not found persuasive. The statement that peptides containing as few as 3 arginine residues were demonstrated to be efficiently internalized does not amount to a disclosure that two arginine residues cannot provide cellular penetration (no teaching away). Applicant has not identified evidence demonstrating that reducing the number from three to two would render the cyclic peptide incapable of cellular uptake. The presently claimed cyclic peptide also retains 2 strongly cationic arginine side chains and therefore remains positively charged. Thus, the proposed construct comprising two arginine residues provide approximately +2 side chain charge while the retained phenylalanine and Nal residues provide substantial hydrophobic/aromatic character. Thus, reducing arginine content does not eliminate either the cationic or hydrophobic characteristics associated with the CPP scaffold.
Applicant argues Rothbard concerns linear peptides and therefore would not be combined with Qian’s cyclic CPP. Applicant argues that teachings regarding flexibility in arginine spacing and linear peptides would not reasonably be applied to a constrained cyclic CPP.
Applicants arguments have been fully considered but not found persuasive. Rothbard is not relied upon as teaching that the linear peptide itself should be substituted for Qian’s cyclic scaffold. Rothbard is relied upon for the more limited teaching that the spatial arrangement separation of arginine residues influences cellular uptake and that incorporation of non-arginine residues between arginine residues can alter uptake behavior. A person of ordinary skill seeking to optimize the cellular uptake characteristics of Qian’s arginine containing CPP would have considered known relationships between arginine number, spacing and cellular uptake when varying the amino acid composition of the cyclic peptides.
Applicant argues that Qian and Qian* allegedly teach that more rigid cyclic peptides exhibit superior membrane interaction whereas Rothbard associates increased spacing flexibility with improved uptake. Applicant therefore argues that Rothbard teaches in a direction inconsistent with Qian.
Applicants arguments have been fully considered but not found persuasive. The proposed modification does not require disregarding Qian’s cyclic constraint or converting the molecule into Rothbard's flexible linear polyarginine peptide. The proposed peptide remains cyclic. Replacement of selected arginine residues with non-arginine residues including glycine, as taught in connection with arginine spacing, represents modification within the retained cyclic scaffold. The rejection need not establish that every property identified by every reference is simultaneously maximized. The issue is whether the skilled artisan would have a reason to vary known structural parameters affecting cellular uptake with a reasonable expectation of obtaining a functioning CPP.
Applicant argues examiners impermissible hindsight to construct the claim sequence. Applicants arguments have been fully considered but not found persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Qian provides the starting cyclic CPP scaffold, the cited art identifies arginine content and arrangement as parameters affecting cellular uptake and Rothbard provides evidence concerning separation of arginine residues by non-arginine residues (such as glycine). The proposed sequence illustrates the predictable products of applying those teachings to Qian’s scaffold and are not relied upon as independently disclosed prior sequences. The existence of multiple possible optimized arrangements does not establish non-obviousness where the claimed arrangement represents one of a finite number of modifications obtained by varying known amino acid positions and compositions for their recognized effect.
Applicant argues there would be no reasonable expectation that arginine cyclic peptide with two arginines would retain permeability. Applicants arguments have been fully considered but not found persuasive. Applicant has not demonstrated that two arginine residues would have been expected to render the cyclic peptide nonfunctional. The prior art establishes that arginine number and arrangement influence uptake thereby motivating optimization of those parameters. The proposed modification does not remove the cationic character of the peptide. Two arginine residues remain protonated under physiological conditions and provide substantial positive charge, while retaining the phenylalanine and Nap residue hydrophobic character. A reasonable expectation of success does not require certainty or an expectation that the modified peptide would outperform Qian’s preferred embodiments. The skilled artisan need only reasonably expect the modified contract to remain useful for its intended purpose (see MPEP 2143 II).
Applicant argues the amended claim requires that targeting moiety to be part of the exocyclic cargo. Applicants arguments have been fully considered but not found persuasive. Pei is additionally relied upon for the teaching of incorporating a targeting moiety into a CPP associated cargo construct. A person of ordinary skill would have had reason to incorporate Pei’s targeting functionality into Qian’s cargo bearing CPP to provide selective delivery of the therapeutic cargo to a desired cellular target. Thus, applicant’s amendment does not overcome the combination because the additional reference addresses the feature under applicants proposed construction.
Applicant argues that Pei still does not disclose the claim peptide as a whole. Applicants argument has been fully considered but not found persuasive. The argument attacks the reference individually rather than the combined teachings underlying the 103 rejection. Pei is not relied upon as independently teaching formula 3B, exactly 2 Arginine residues, Qian’s glutamine conjugation and every cargo component. Rather Qian supplies the principal cyclic CPP cargo scaffold, Qian* and Rothbard supply the teachings concerning optimization of arginine content and arrangement and Pei supplies the targeting moiety teaching. The question under 103 is what the combined teachings would have suggested to a person of ordinary skill not whether a single secondary reference independently anticipates the claim dimension.
MPEP 2145 IV states “One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).”
Applicants evidence demonstrates that arginine number and arrangement affect cellular uptake which is consistent with the examiner's findings that these structural characteristics were known parameters relevant to CPP performance. Although applicant identifies embodiments containing 3 or more arginine residues, applicant has not established that the cited art criticizes discredits or otherwise discourages cyclic CPPs containing 2 arginine residues nor has applicant established that two arginine residues would have been expected to render the peptide incapable of cellular uptake. Proposed modification retains the cyclic scaffold, 2 cationic arginine residues and hydrophobic/aromatic residues of the Qian type CPP, while applying the prior arts teachings concerning arginine number and spacing.
Conclusion
No claims are allowed.
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 ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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