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 .
Election/Restrictions
This application contains claims directed to the following patentably distinct species:
Fibrosis and angiogenesis, and
SEQ ID No: 2-7, 17-23 and 27-34.
Fibrosis and angiogenesis are independent or distinct species because these are distinct pathologies with distinct mechanisms. These would require distinct prior art searches and enablement considerations. In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, none of the claims are generic.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: Fibrosis and angiogenesis are distinct pathologies with distinct mechanisms. The search for each of the above inventions is not co-extensive particularly with regard to the literature search. Further, a reference, which would anticipate the invention of one group would not necessarily anticipate or even make obvious another group. These would also require separate enablement consideration.
SEQ ID No: 2-7, 17-23 and 27-34 are independent or distinct species because these are distinct peptide sequences derived from distinct CXCL peptide with distinct mutations that result in cleavage sites for distinct proteases. These would require distinct prior art searches and enablement considerations. In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, claims 1-12, 16-20 are generic.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: SEQ ID No: 2-7, 17-23 and 27-34 are distinct peptide sequences derived from distinct CXCL peptide with distinct mutations that result in cleavage sites for distinct proteases. The search for each of the above inventions is not co-extensive particularly with regard to the literature search. Further, a reference, which would anticipate the invention of one group would not necessarily anticipate or even make obvious another group. These would also require separate enablement consideration.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
During a telephone conversation with Jodi Connolly on 8/4/2026 a provisional election was made without traverse to prosecute species “angiogenesis”, claims 1, 4-20, and “SEQ ID NO. 2” in claims 13, 14.
Affirmation of this election must be made by applicant in replying to this Office action.
Claims 2-3, as directed to non-elected species of fibrosis, are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Peptide 102, 105, 106, 107 are mentioned in the example 1 as positive controls but no sequence for any of these peptides are disclosed and thus no sequence identifiers are identified.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: Peptide 102, 105, 106, 107 are mentioned in the example 1 as positive controls but no sequence for any of these peptides are disclosed such that the data for this example could be properly evaluated. A positive control is a condition that is known to cause the effect measured in the experiment. In example 1, peptide 105-107 fail to inhibit angiogenesis, thus their validity as positive controls is hard to evaluate, especially because their structure is unknown.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10, 11, 14 and 15 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.
The term “about” in claims 10 and 11 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Due to the use of this relative term, the range of peptide lengths embraced by the claims is rendered indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 14 and 15 recite the broad recitation of “comprises […] SEQ ID NOs: 2-7 [..]”, and the claim also recites “consists of […] SEQ ID NOs: 2-7 [..]” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 1, 4-20 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. 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 1, 4, 5 embraces any CXCL protein or its peptide fragment that is modified in comparison to a wild-type CXCL protein such that it comprises any cleavage site for any protease. The modification is not limited, and embraces insertion, substitution and deletion of any one or more amino acid residues. Furthermore, the modification can result in a cleavage site recognized by any protease. No specific guidance is provided regarding cleavage site. Song et al (PLoS One 7(11):e50300, 2012; cited in IDS dated 8/28/2024) provides teachings pertaining to cleavage site of various proteases. Song teaches that 16 amino acid residues surrounding the scissile bond (cleaved by protease that is between residue P1 and P1’) could be part of the cleavage site for a protease that may impact the cleavage efficacy to different extent (see Figure 3H below, size of letters indicate impact). Thus, modification resulting in a cleavage site recognized by any protease embraces insertion, deletion or substitution of any number of residues from the wild-type protein such that a cleavage site recognized by any protease results. Additionally, the claim embraces any peptide fragment of a wild-type CXCL protein. Taken together, the claims embrace an expansive array of recombinant CXCL peptides. Critically, the claim requires these peptides to function as anti-angiogenic or angiostatic.
Claims 6-9 limits the proteases of claim 1. However, as noted above, no specific guidance is provided regarding cleavage site while Song teaches that a cleavage site could include up to 16 residues surrounding the scissile bond. Further, no specific modification type (insertion, deletion or substitution) is required. Taken together, claims 6-9 embrace CXCL peptides that comprise insertion, deletion or substitution of any number of residues from the wild-type protein such that a cleavage site recognized by the claimed protease results. Claims 6-9 also embrace an expansive array of recombinant CXCL peptides. Critically, the claim requires these peptides to function as anti-angiogenic or angiostatic.
Claim 10-12 limit the length of the peptide fragment and thus embrace any peptide fragment of a wild-type CXCL protein as long as it is within the specified length range. Thus, these claims embrace a similar expansive breadth as claim 1 but limited to any peptide fragment of the recited length. There is no guidance regarding how to choose a functional peptide that would be functional in the claimed method of treating excess angiogenesis.
Claims 13-15 recite specific peptide sequences (SEQ ID NOs: 2-7, 17-23 and 27-34). These sequences are peptide fragments of wild-type CXCL4, 10 or 11 proteins comprising substitution mutations resulting in cleavage sites for cathepsin G, neutrophil elastase, MMP2, cathepsin K (p. 17-20). However, the claims are not limited to these sequences but embraces any peptide that is at least 90% identical to any one of these sequences, as in claim 14, or any protein or peptide fragment that comprises the recited peptide fragments.
Claims 16-20 introduce additional limitation regarding chemical modifications or slow-release formulation without narrowing the limitations recited in claim 1. Thus, these claims embrace the same expansive breadth as claim 1.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by “whatever characteristics sufficiently distinguish if). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G. D. Searie & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). See MPEP § 2163.
In the instant case, the disclosure is limited to only ligand of human CXCR3 and not any CXCL peptide as broadly claimed. “This disclosure concerns peptide activators of C-X-C chemokine receptor 3 (CXCR3) that can be cleaved by proteases present at sites of inflammation” (Field). Further, in the summary, the specification states that “Described herein are recombinant C-X-C motif chemokine ligand (CXCL) peptides that are modified to introduce a cleavage site for a protease, such as a protease activated during an inflammatory response. The disclosed peptides have the capacity to activate CXCR3 until being cleaved by the protease.” (Summary, para 1). In the detailed description, “Provided herein are recombinant C-X-C motif chemokine ligand (CXCL) peptides that are modified relative to a wild-type CXCL amino acid sequence to introduce a cleavage site for a protease. In some embodiments, the CXCL is a ligand for C-X-C chemokine receptor 3 (CXCR3). In some examples, the CXCL is CXCL10, CXCL4, CXCL9 or CXCL11. In specific non-limiting examples, the CXCL is CXCL10” (page 12, para 3). Finally, each of the disclosed peptide sequences is directed to a CXCL peptide activator of CXCR3 derived from one of four CXCL proteins (CXCL4, CXCL10, CXCL9, CXCL11). When describing the disclosed peptide sequences, the specification states “The present disclosure describes modified peptides derived from a CXCL protein that functions as a ligand for CXCR3” (page 15, para 1). Sequences for 4 human CXCL proteins namely CXCL4, CXCL9, CXCL10, CXCL11, each an activator of CXCR3, are disclosed as SEQ ID Nos. 8-11.
However, disclosure of only CXCR3-activating human CXCL proteins is not representative for any CXCL proteins. Nomiyama et al (The evolution of mammalian chemokine genes. Cytokine and Growth Factor Reviews, Volume 21, 2010; herein after Nomiyama 2010; IDS 8/28/2024) teaches that in humans, 17 distinct CXCL genes encoding 17 distinct CXCL proteins with distinct functions. Of the 17 human CXCL protein, Nomiyama teaches only 4 CXCL proteins interact with CXCR3 while other CXCL proteins interact with other CXC receptors (Figure 1, Table 1). Therefore, disclosure of only CXCR3-activating human CXCL proteins is not representative for any human CXCL proteins. In a subsequent publication, Nomiyama et al (Systematic classification of vertebrate chemokines based on conserved synteny and evolutionary history. Genes to Cells, 2013; cited in IDS dated 8/28/2024; hereinafter Nomiyama 2013) teaches nearly 554 genes within 18 vertebrate species. Regarding the chemokines identified, they teach that “most of these are species- or lineage-specific chemokines”, of which CXCL chemokines can classified into at least 46 distinct groups (Table 1). The lack of structural similarity across species is also evident from the sequence alignment shown above for human and mouse CXCL10 proteins that only share 68% homology.
Peptide variants of only CXCL4, CXCL9, CXCL10, CXCL11 human proteins are disclosed (SEQ ID NOs: 2-7, 17-23, 27-34; recited in claims 14-15). These sequences are peptide fragments of wild-type CXCL4, 10 or 11 proteins comprising only substitution mutations resulting in cleavage sites for cathepsin G, neutrophil elastase, MMP2, cathepsin K (p. 17-20). Although SEQ ID NO: 2, a well-known peptide fragment of CXCL10 variant with a cathepsin G protease site, was tested for functionality in example 1, no other peptide fragment was tested.
However, the prior art taught that modification of even one residue can have significant impact on the function of a protein such that no clear structure-function relationship exists between modifications and the functional outcome. Lucchese et al (How a single amino acid change may alter the immunological information of a peptide. Frontiers in Bioscience E4, 1843-1852, January 1, 2012) teaches that “The functional importance of even a single amino acid (aa) substitution is evident at both the physiological and pathological levels” teaching several well-known examples of proteins and peptides in which just a single mutation had significant functional impact (p. 1843, col. 2). Nomiyama 2010 teaches that modifications to only a few residues can have significant impact on the function of the CXCL peptide. For example, regarding human CXCL4 and its variant CXCL4L1, they note that “CXCL4 and CXCL4L1 differ in only three amino acids, but they are expressed and secreted in a differentially regulated manner and exhibit a distinct subcellular localization. Moreover, CXCL4L1 has more profound effects in blocking angiogenesis” (page 256, right column, para 3). Furthermore, Song taught that specificity of protease is not merely dependent on the cleavage site but the three-dimensional structure of the protein and location of the cleavage site in the protein are also important (p. 1 col. 2). Thus, modification of a peptide to comprise even a single substitution mutation could not only alter its function but may not result in a cleavage site recognized by the desired protease depending on the location of the mutation, the type of mutation and the structure of the peptide. This is especially the case when the recited SEQ ID NOs: 2-7, 17-23, 27-34 could be comprised within a longer sequence resulting in a distinct secondary structure.
Regarding species of recombinant CXCL peptides that are at least 90% identical to any one of 21 sequences (SEQ ID Nos: 2-7, 17-23 and 27-34), the specification only discloses species that are 100% identical to the recited SEQ ID Nos. However, CXCL peptides with 100-90% identity to the recited sequences can vary substantially. There is no teaching in the specification in which 10% of the structure can be varied while retaining the ability of the peptide to function as a CXCL peptide. Consequently, there is no information about which residues can vary from the recited sequences, in the claimed genus of nucleotide sequences, fragments and variants and still retain the activity and function of a CXCL peptide. The specification only describes the full length sequences of SEQ ID Nos: 2-7, 17-23 and 27-34 and fails to teach or describe any other variant sequences, that comprise these sequences or are less than 100% identical to them, having the activity presumably possessed by the SEQ ID Nos: 2-7, 17-23 and 27-34. Only SEQ ID NO: 2 is shown to be functional.
Furthermore, the disclosure does not provide any distinguishing identifying characteristics of the species embraced by the claims; such as by identifying critical residues or domains. Owing to significant variation in structure and function of CXCL proteins in humans and across species and, the lack of structural and functional relationship between CXCL proteins/ variants and the exhibited function, a skilled artisan cannot envision the species embraced by the claims, including any fragment/variant that comprises or shares 90% similarity with any one of the SEQ ID Nos: 2-7, 17-23 and 27-34. A skilled artisan cannot envision the structures embraced by expansive array of peptides embraced by the claims that are also required to perform anti-angiogenic or angiostatic function. The specification discloses CXCL peptides that are 100% identical to SEQ ID NOs: 2-7, 17-23, 27-34. No distinguishing identifying characteristics that establish a structure-function relationship is disclosed. The prior art clearly teaches that a predictable structure-function relationship cannot be established.
Therefore, the claimed invention, as a whole, is not adequately described. In the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus.
Scope of Enablement
Claims 1, 4-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of inhibiting corneal neovascularization in a subject, comprising administering to the eye of the subject a recombinant C-X-C motif chemokine ligand (CXCL) peptide comprising a modification relative to a wild-type CXCL amino acid sequence, wherein the modification is a cleavage site for a protease;
wherein the peptide consists of SEQ ID NO: 2.,
does not reasonably provide enablement for a method inhibiting angiogenesis in any tissue arising due to any disease, comprising administration via any route and any CXCL peptide as broadly claimed .
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
With respect to the breadth of the claims: Claim 1 as currently drafted encompass a method that inhibits angiogenesis in any tissue of a subject arising due to any disease or disorder. The method accomplishes this by administering any CXCL peptide from any species via any route as long as the CXCL peptide comprises any type of modification in comparison to any wild-type CXCL that results in a cleavage site for any protease. Thus, the breadth of this claim is expansive.
Claim 4, 5 repeat that the method of claim 1 is for inhibiting angiogenesis and that the subject has an angiogenic disorder of the eye but do not require that the method inhibit angiogenesis in the eye, the route of administration of the peptide and the peptide itself. Thus, the breadth of these claims is expansive.
Claims 6-9 limits the proteases of claim 1. However, the claims do not recite any specific modification in the peptide that results in a cleavage site identified by these proteases. There is no guidance which of these proteases are related to which angiogenic disorder. These claims continue to embrace a method that inhibits angiogenesis in any tissue arising due to any disease or disorder, any route of administration of the peptide and any peptide itself as long it has any modification that results in a site that is cleaved by the recite protease. Thus, the breadth of these claims is expansive.
Claim 10-12 limit the length of the peptide fragment and thus embrace any peptide fragment of a wild-type CXCL protein as long as it is within the specified length range. There is no guidance regarding how to choose a functional peptide that would be functional in the claimed method of treating excess angiogenesis. These claims continue to embrace a method that inhibits angiogenesis in any tissue arising due to any disease or disorder, any route of administration of the peptide and any peptide itself as long it has any modification that results in a site that is cleaved by the recite protease. Thus, the breadth of these claims is expansive.
Claims 13-15 recite specific peptide sequences (SEQ ID NOs: 2-7, 17-23 and 27-34). These sequences are peptide fragments of wild-type CXCL4, 10 or 11 proteins comprising substitution mutations resulting in cleavage sites for cathepsin G, neutrophil elastase, MMP2, cathepsin K (p. 17-20). However, the claims are not limited to these sequences but embraces any peptide that is at least 90% identical to any one of these sequences, as in claim 14, or any protein or peptide fragment that comprises the recited peptide fragments. Furthermore, these claims continue to embrace a method that inhibits angiogenesis in any tissue arising due to any disease or disorder and any route of administration of the peptide. Thus, the breadth of these claims is broad.
Claims 16-20 introduce additional limitation regarding chemical modifications or slow-release formulation without narrowing the limitations recited in claim 1. Thus, these claims embrace the same expansive breadth as claim 1.
(B) The nature of the invention: The invention is in the field of therapeutic peptides and peptide engineering to produce protease cleavable peptides.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Angiostatic effects of ELR-ve CXCL peptides that activate CXCR3 were known. Belperio et al (CXC chemokines in angiogenesis. Journal of Leukocyte Biology Volume 68, July 2000) provides a literature of CXC chemokines and their variable receptors and distinct functional effects. Several CXC chemokines are pro-angiogenesis while some are known to have anti-angiogenic or angiostatic effects (Table 1). Specifically, CXC chemokines that lack the ELR motif, such as CXCL4, 9 and 10 (Table 1, PF4 =CXCL4, MIG = CXCL9, IP-10 =CXCL10). Other ELR-ve CXC chemokines that showed promise were CXCl11 (=ITAC; p. 2, col. 2, ¶ 3). The primary mechanism of action for angiostatic effect of these ELR-ve chemokines is via VEGF inhibition (p. 3, col. 2, ¶ 1). These have been shown to inhibit angiogenesis in several cancer model systems with or without T-cell infiltration (p. 4, col. 2, ¶ 2). Specifically, CXCL10 depletion from carcinoma models increases angiogenesis and CXCL10 levels are inversely correlated with patient outcomes (p. 4, col. 2, ¶ 3). Increase of CXCL10 in adenocarcinoma tumor reduces angiogenesis and tumor growth unrelated to immune cell infiltration (p. 5, col. 1, ¶ 1). However, the ability of ELR-ve chemokines, specifically CXCL10 to recruit immune cells to a cancer is also important for its functional effect in reducing tumor burden. Balestrieri et al (Understanding the immunoangiostatic CXC chemokine Network. Cardiovascular Research (2008) 78, 250–256) teaches the immunoangiostatic effect of CXCL chemokines in cancer wherein CXCR3-expressing immune cells are recruited to the tumor site (Table 1, Figure 3 and Section 4). Thus, therapeutic effect of ELR-ve CXC chemokines in cancer is due to their angiostatic and immune cell-attractant effects. Introduction of a cleavage site to a protease activated during an inflammatory response in a CXCL peptide, as suggested by the instant disclosure in the summary section, if effective, has the potential to reduce the efficacy of the peptide for cancer.
However, harnessing CXCL10’s angiostatic abilities without also potentially attracting and proliferating immune cells could be done by using a CXCL10 peptide fragment. Yates-Binder et al (An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis. PLoS One, Vol. 7, July 2012) taught that CXCR3 isoforms A and B differentially regulate cell function with isoform A regulating chemotaxis and proliferation of various cells and isoform B primarily responsible for inhibiting migration, inducing apoptosis of endothelial cells (p.1, col. 1, ¶ 2). They teach that full-length CXCL10 binds both isoforms while a 22 amino acid peptide fragment binds CXCR3 (p.1, col. 2, ¶ 1, last sentence). They teach that the CXCL10 peptide fragment comprises the a-helix domain of the full-length of CXCL10 protein and functions same as the full-length in inhibiting angiogenesis (Figure 1, 8).
Use of CXCL10 to inhibit corneal neovascularization (CNV) was also known. Gao et al (CXCL10 suppression of hem- and lymph-angiogenesis in inflamed corneas through MMP13. Angiogenesis (2017) 20:505–518) show that increasing CXCL10 expression by viral vectors encoding CXCL10 injected directly to the eye inhibits infection-induced and injury-induced CNV (Figure 1, 4). Other injury induced CNV models show similar effects of CXCL10. Liu et al (Critical Role of IP-10 on Reducing Experimental Corneal Neovascularization. Current Eye Research, 2015; 40(9): 891–901) taught increase in CXCL10 levels 2-4 days after injury while topical application of CXCL10 protein directly to the eye immediately after injury reduced neovascularization (Figure 1, 2). They also teach that in injury-induced CNV immediate application of CXCL10 after injury resulted in reduction pro-inflammatory cytokines such as TNFa and IL-6 over time (Figure 3). They show that although similar number of macrophages accumulated in both control and CXCL10 treated corneas, VEGF +ve macrophages were significantly reduced in CXCL10 treated corneas (Figure 5). Liu also reference previous publication wherein CXCL10 was delivered by direct injection the eye (p. 900, col. 1, ¶ 1).
Taken together, the art teaches angiostatic effect of ELR -ve CXC protein that activate CXCR3 in cancer and angiogenic-eye disease model. The art also teaches a CXCL10 peptide that retains angiostatic functions. However, the art does not teach any peptide fragment of a CXCL, especially one that is modified in any way to introduce any cleavage site to any protease could be used to inhibit angiogenesis in any disease model, including CNV. This is because it is unpredictable which fragments of the broadly claimed CXCL protein would retain angiostatic function. Further, there is no predictability that any of these CXCL peptide fragments when modified would retain their angiostatic function. Finally, there is no predictability that introduction of any cleavage site for any protease would achieve therapeutic efficacy.
The prior art taught that modification of even one residue can have significant impact on the function of a protein such that it is unpredictable which modifications would retain the desired peptide function. Lucchese teaches that “The functional importance of even a single amino acid (aa) substitution is evident at both the physiological and pathological levels” teaching several well-known examples of proteins and peptides in which just a single mutation had significant functional impact (p. 1843, col. 2). Nomiyama 2010 teaches that modifications to only a few residues can have significant impact on the function of the CXCL peptide. For example, regarding human CXCL4 and its variant CXCL4L1, they note that “CXCL4 and CXCL4L1 differ in only three amino acids, but they are expressed and secreted in a differentially regulated manner and exhibit a distinct subcellular localization. Moreover, CXCL4L1 has more profound effects in blocking angiogenesis” (page 256, right column, para 3). Furthermore, Song taught that specificity of protease is not merely dependent on the cleavage site but the three-dimensional structure of the protein and location of the cleavage site in the protein are also important (p. 1 col. 2). Thus, modification of a peptide to comprise even a single substitution mutation could not only alter its function but may not result in a cleavage site recognized by the desired protease depending on the location of the mutation, the type of mutation and the structure of the peptide. This is especially the case when the recited SEQ ID NOs: 2-7, 17-23, 27-34 could be comprised within a longer sequence resulting in a distinct secondary structure. Critical for an in vivo method of treating, Song also taught that protease activity is also context dependent, being regulated by co-factors and ligands which may vary depending on route of administration and target tissue (p. 2, col. 1, ¶ 1). Thus, not only is there no predictability that a modified CXCL peptide fragment would be angiostatic, but there is also no predictability that a protease-site introduced by any modification would be effectively cleaved by the protease and if it is cleaved then this function would be retained in vivo resulting in the expected therapeutic outcome.
Therefore, the prior art teaches high degree of unpredictability in ascertaining which of the broadly claimed peptides would result in reduced angiogenesis.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The applicants have provided one working example directed to inhibiting CNV by injecting peptide 110 that consists of SEQ ID NO: 2 immediately after injury directly to the eye (Example 1, Figure 1, 2). Although peptide 110 has one substitution mutation that results in a cathepsin G and neutrophil elastase cleavage site (p. 26), there is no data that shows that peptide 110 is actually cleaved by either of these proteases in vitro or in vivo.
The applicants have not provided evidence that any of the other peptides of SEQ ID NO: 3-7, 17-23, 27-34 are anti-angiostatic. Each of these peptides comprise different cleavages sits to different proteases (p. 26-27) but there is no evidence that these proteases cleave these peptides and if so, which one would be effective in which tissue and if any would be effective in CNV. A peptide with a highly effective cleavage site to a protease that is highly expressed in the eye may be cleaved before it has any effect or may result in a fragment with a distinct, unpredictable effect.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its unpredictability, and the limited amount of guidance in the form of varied working examples in the specification.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1, 4-20, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1, 4-20 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make and use the invention to its full scope.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632
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