DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgments are made that this application claims the priority to the following:
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Information Disclosure Statement
The filed information disclosure statements (IDS) comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Response to Restriction
Applicant's response to election of species in the reply filed on 02/12/2026 is acknowledged.
Applicant’s election of the cyclic cell penetrating peptide cyclo(RFFFRRRQ) (SEQ ID NO: 263) conjugated through the glutamine to the exocyclic cargo moiety PΘGΛYR (SEQ ID NO: 89), wherein Θ is L-homoproline and Λ is L-4-(phosphonodifluoromethyl)phenylalanine, is acknowledged.
Following an extensive search and examination, the originally elected species has been deemed free of the prior art.
Per MPEP § 803.02, “If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended”. Here, examination was subsequently extended to all species encompassed by the claimed cyclic cell penetrating 8 amino acid peptide with the recited limitations. Each of these compounds was subsequently deemed free of the prior art. Accordingly, Examination has proceeded to the broadest genus of record as set forth at instant claim 1. The broadest genus has been rejected under 35 USC 112(a) as explained below.
The claims 1-16 are examined on merits in this office action.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement for the claimed method. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:
Independent claim 1 is drawn to a compound comprising: (i) a cyclic cell penetrating 8 amino acid peptide that contains, (a) one arginine within two amino acids of another arginine, and (b) an amino acid with a hydrophobic side chain within two amino acids of another amino acid with a hydrophobic side chain; and (ii) an exocyclic cargo moiety conjugated to a side chain of the cell penetrating peptide wherein the conjugation is through glutamine and wherein the cargo comprises an amino acid sequence that targets an enzyme.
Dependent claims further limit the variables of independent claim with the recited sub-genus species.
No claim recites species for the claimed compound, and also no claim recites species or complete structure for the cyclic cell penetrating 8 amino acid peptide and cargo moiety. Claims are structured as a quiz language without any clue.
Both cyclic cell penetrating peptide and exocyclic cargo moiety are associated with the recited properties. However, there is no defined core structure for the claimed compound, cyclic cell penetrating 8 amino acid peptide and exocyclic cargo moiety.
Claims recite Arg, Phe, Gly, Gln and napthylalanine as possible moieties in the claimed cyclic peptide and the remaining can be any amino acids. Similarly, no clear definition for cargo, and cargo can have additional therapeutic, linker and detectable moieties.
The core structure is responsible for the properties of individual moieties and these are associated with property of claimed compound as a whole, and in its absence of clear definition makes the invention unpredictable, and cannot be understood by a skilled person in the art.
Specification described cyclic cell penetrating peptides with Formula I, and in all these structures any two adjacent amino acid residues are the beta-hairpin turn creating moiety, viz., D-Pro-L-Pro or L-Pro-D-Pro. No such limitations are present in the claimed subject matter.
Specification described cargo moiety broadly and no definitive definition is provided. Table 4 lists some cargo sequences. However, table does not recite applicants elected species. Table 5 lists targeting moieties, which are part of cargo moiety accordingly to the description.
Only Table 11 in the specification lists cyclic cell penetrating 8 amino acid peptides, see SEQ ID NOs: 260-267 and their properties. No description or data is shown with claimed conjugated cargo moiety with these sequences. No species or examples in the specification are provided for the claimed compound.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the genus or broadly claimed subject matter, and if the variability expects unpredictability for the claimed subject matter, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed invention. In this case, protein chemistry is probably one of the most unpredictable areas of biotechnology and consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. So, the absence of description with divergent species makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP 2163 II(A)(3)(a)(ii).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described.
The question is with thousands of possible divergent compounds can be generated based on the claim language, with all possible amino acids in the cyclic peptides other than recited ones, in all possible combinations, (i) did applicants provide enough description for making all possible conjugates with all possible peptides with all possible linkers? (ii) will the generated divergent conjugates be capable of retain its end property? Based (i) and/or (ii), will a skilled person in the art understand the claimed invention?
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Not provided. The claimed genus of compounds with genus of cyclic cell penetrating 8 amino acids peptides and cargo can generate unlimited number of conjugates. The specification described or shown only cyclic peptides in Table 11, not the claimed conjugates or compounds.
So, the provided data is very limited to cyclic peptides, and no description or evidence is provided, specifically nexus between shown data in Table 11 can be extrapolated to the claimed conjugates or compounds, and the resulted ones can retain the end property.
Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
None of the shown drawings or figures describe claimed compound or cyclic cell penetrating 8 amino acid peptide.
In other words figures are limited to 10 or more amino acid cyclic peptides. Fig. 10A shows cyclic cell penetrating peptide with 8 amino acids, but it does not have Arg.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
Though the claimed individual compounds or conjugate and their synthetic methods are known, but the coupling or cross linking the with all possible linkers are unpredictable. The reaction conditions for divergent cargo moieties and linkers are expected to be different. These are in turn effect the coupling or cross linking chemistry. Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ 367 3. The described synthetic methodology is very generic.
With regard to amino acid sequences in the cyclic peptides and cargo moieties in the claimed compounds or conjugates, protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
With regard to linkers, the properties of conjugates are sensitive to the linker moiety [see section 6 in He et al, Molecules, 2019, 24, 1855, 1-34; see abstract and conclusion in Lu et al, International Journal of Molecular Sciences, 2016, 17, 561, 1-22].
The art also recognizes that the choice of a linker has great impacts on biological activity, expression yield, and pharmacokinetic properties of a fusion partner (see Chen et al. Adv. Drug Deliv. Rev. 65:1357-1369, 2013).
Verdine et al (Methods in Enzymology, 2012, vol.503, 3-33) also showed or described possible unpredictability in staples in the peptide conjugates [see sections 3-5 and 13-14].
Applicants are reminded that in the above cited references, the publication date is irrelevant, when showing the evidence.
In view of above evidences, applicants have claimed unlimited range of conjugates and a skilled person in the art can expect unpredictability in the broadly claimed genus. There are no physical/chemical/structural features that applicants have tied to this property in a relevant teaching manner, and so, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed conjugates would retain its end property. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Nonstatutory Double Patenting Rejection
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(i) Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US 11,352,394 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
For claim 1:
Claims 1-8 and 21 of US patent teaches a compound comprising a cyclic peptide having 8 amino acids comprising a cell penetrating peptide moiety, represented by the following structure:
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, wherein AA1-AA8 are amino acids, wherein at least three amino acids are Arg, at least three amino acids comprises a hydrophobic side chain.
Claims further teach that the compound further comprises cargo moiety.
For claims 2-4:
Claim 10 of US patent teaches that the amino acid residues comprising a hydrophobic side chain are independently residues of 3-benzothienyl-L-alanine, phenylalanine, naphthylalanine, or tryptophan, each of which is optionally substituted. These hydrophobic side chains are expected to participate in pi-stacking.
For claims 5-7:
Claim 20 of US patent teaches cargo, but silent on linker, therapeutic and detectable moieties on the cargo.
However, specification defined cargo, which comprises linker, therapeutic and detectable moieties [see col.7, lines 9-42; col.28, lines 45-67].
For claims 8-13:
Claim 10 of US patent teaches that the amino acid residues comprising a hydrophobic side chain are independently residues of 3-benzothienyl-L-alanine, phenylalanine, naphthylalanine, or tryptophan, each of which is optionally substituted.
Claims 17 and 18 teaches that two amino acid residues which comprise a hydrophobic side chain are consecutive.
Though claims of US patent silent on glycine, but glycine is obvious over alanine, since the difference can be characterized as H vs methyl group. The issue of patentability over the replacement of alkyl groups for hydrogen has arisen many times. For instance, the replacement of a methylene group with a dialkyl-substituted methylene group was determined to be prima facie obvious on the ground that "one skilled in the art would have been, prima facie, motivated to make the claimed compounds in the expectation that they, too, would possess antimicrobial activity." (In re Wood 199 USPQ 137) See also In re Doebel 174 USPQ 158 (where replacement of methyl for hydrogen on an amino nitrogen was considered prima facie obvious - at page 159); In re Druey 138 USPQ 39 (where replacement of methyl for hydrogen on a known compound was considered prima face obvious based on the homologous and close structural relationship to the known compound - at page 41); In re Lohr 137 USPQ 548 (where the replacement of a methyl group for a hydrogen on two positions of a tetrahydropyran ring on a known compound was not considered a patentable modification given the close structural relationship to the known compounds - at page 550); Ex parte Bluestone 135 USPQ 199 (where fungicidal compounds differing by hydrogen versus methyl on the nitrogen of a thiazolidine-2-thione ring were considered homologs and were not found to be patentable over each other without a showing of unexpected results - at page 200); Ex parte Weston 121 USPQ 429 (where the replacement of methyl for hydrogen on the nitrogen of a piperazine ring was not found to be a patentable modification).
For claims 14-16:
At least claims 17-18 of US patent teaches amino acids are natural amino acids and coupled by peptide bonds and consecutive L-amino acids.
Based on the above, the subject matter claimed in the instant application is fully disclosed and covered in the claims of US patent. It appears that the claims of US patent are broader in scope, whereas the claims of instant claims are narrow in scope. The difference, however, does not constitute a patentable distinct, because the scope overlaps, and skilled person in the art would be motivated to make the compound of instant application in light of guidance provided by the US patent. Therefore, claims are obvious over the claims of US patent.
(ii) Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US 12,454,552 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
For claim 1:
Claim 1 of US patent teaches a compound comprising a cyclic peptide having 8 amino acids, represented by the following structure:
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, wherein AA1-AA8 are amino acids, wherein at least three amino acids are Arg, at least two or more amino acids comprises a hydrophobic side chain.
Claim 3 teaches that the compound further comprises cargo moiety.
For claims 2-4:
Claim 1 of US patent teaches that the amino acids having hydrophobic side chains are each independently phenylalanine and naphthylalanine. These hydrophobic side chains are expected to participate in pi-stacking.
For claims 5-7:
Claim 3 of US patent teaches cargo, but silent on linker, therapeutic and detectable moieties on the cargo.
However, specification defined cargo, which comprises linker, therapeutic and detectable moieties [see col.7, lines 1-32; col.28, lines 44-67].
For claims 8-13:
Claim 1 of US patent teaches that the amino acid residues comprising a hydrophobic side chain are independently residues of phenylalanine, naphthylalanine.
Claim 7 teaches that two amino acid residues which comprise a hydrophobic side chain are consecutive.
Though claims of US patent silent on glycine, but glycine is obvious over alanine, since the difference can be characterized as H vs methyl group. The issue of patentability over the replacement of alkyl groups for hydrogen has arisen many times. For instance, the replacement of a methylene group with a dialkyl-substituted methylene group was determined to be prima facie obvious on the ground that "one skilled in the art would have been, prima facie, motivated to make the claimed compounds in the expectation that they, too, would possess antimicrobial activity." (In re Wood 199 USPQ 137) See also In re Doebel 174 USPQ 158 (where replacement of methyl for hydrogen on an amino nitrogen was considered prima facie obvious - at page 159); In re Druey 138 USPQ 39 (where replacement of methyl for hydrogen on a known compound was considered prima face obvious based on the homologous and close structural relationship to the known compound - at page 41); In re Lohr 137 USPQ 548 (where the replacement of a methyl group for a hydrogen on two positions of a tetrahydropyran ring on a known compound was not considered a patentable modification given the close structural relationship to the known compounds - at page 550); Ex parte Bluestone 135 USPQ 199 (where fungicidal compounds differing by hydrogen versus methyl on the nitrogen of a thiazolidine-2-thione ring were considered homologs and were not found to be patentable over each other without a showing of unexpected results - at page 200); Ex parte Weston 121 USPQ 429 (where the replacement of methyl for hydrogen on the nitrogen of a piperazine ring was not found to be a patentable modification).
For claims 14-16:
At least claims 17-18 of US patent teaches amino acids are natural amino acids and coupled by peptide bonds and consecutive L-amino acids.
Based on the above, the subject matter claimed in the instant application is fully disclosed and covered in the claims of US patent. It appears that the claims of US patent are broader in scope, whereas the claims of instant claims are narrow in scope. The difference, however, does not constitute a patentable distinct, because the scope overlaps, and skilled person in the art would be motivated to make the compound of instant application in light of guidance provided by the US patent. Therefore, claims are obvious over the claims of US patent.
(iii) Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US copending application number 19/329,410.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
For claim 1:
Claim 1 of US copending application teaches a cyclic peptide having 8 amino acids, represented by the following structure:
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, wherein AA1-AA8 are amino acids, wherein at least two amino acids are Arg, at least two amino acids comprises a hydrophobic side chain.
Claim 1 further teaches that there is a cargo moiety coupled to a side chain of an amino acid, viz., side chain of glutamine in the cyclic peptide.
For claims 2-4:
Claims 2-4 of US copending application teaches that the amino acids having hydrophobic side chains are each independently glycine, phenylalanine and naphthylalanine. These hydrophobic side chains are expected to participate in pi-stacking.
For claims 5-7:
Claim 1 of copending application teaches that the cargo moiety comprises a linker moiety, a therapeutic moiety, and a targeting moiety.
For claims 8-13:
Claim 1 of copending application teaches that AA1-AA8 are amino acids, wherein at least two amino acids are Arg, at least two amino acids comprises a hydrophobic side chain.
Claims 2-4 of US copending application teaches that the amino acids having hydrophobic side chains are each independently glycine, phenylalanine and naphthylalanine.
Claim 12 of copending application teaches that at least two are consecutive amino acids.
For claims 14-16:
At least claims 12 of copending application teaches that amino acids are natural amino acids and coupled by peptide bonds and consecutive L-amino acids.
Based on the above, the subject matter claimed in the instant application is fully disclosed and covered in the claims of copending application. It appears that the claims of instant application are broader in scope, whereas the claims of copending application are narrow in scope. The difference, however, does not constitute a patentable distinct, because the scope overlaps, and skilled person in the art would be motivated to make the compound of instant application in light of guidance provided by the copending application. Therefore, claims are obvious over the claims of US patent.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not been patented yet.
Conclusion
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/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658