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
Applicant claims domestic benefit under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 63/341,339, filed on 5/12/2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/2/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election with traverse of Claims 1-12 in the reply filed on 11/25/2025 is acknowledged. The traversal is on the grounds that “the groups of claims are so closely interwoven that a search of any one of the groups would uncover all of the prior art relevant to the other groups of inventions”. This is not found persuasive because the restriction was made between distinct categories of invention including a product, a process of making the product and a process of using the product, wherein the product itself can be made in a material different manner and the product has uses distinct from those in the non-elected claims. Restriction is proper because the inventions are independent or distinct and the inventions have different classifications, require distinct fields of searching, and raise different non-prior art issues under 35 U.S.C. § 101 and 112(a), as pointed out in the restriction requirement mailed 9/25/2025. The Applicant’s argument does not specifically point out any errors in the restriction requirement.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/25/2025.
Claim Status
Claims 1-16 are pending. Applicant’s amendments to the claims filed 11/25/2025 is acknowledged and has been entered.
It is noted that the claim amendments filed 11/25/2025 are not in compliance with 37 CFR 1.121(c), because claims 2, 4, 12, and 15 have been amended as compared to the original claims, filed 5/5/2023, but these claims are labeled “(Original)” and not “(Currently amended)”. Further, there are no markings to indicate the changes. The text of any added subject matter must be shown by underlining the added text and any deleted matter must be shown by strike-through (double brackets placed before and after the deleted characters may be used to show deletion of five or fewer characters). The requirements of 37 CFR 1.121(c) are reproduced below.
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of "canceled" or "not entered" may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as "withdrawn— currently amended."
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of "original," "withdrawn" or "previously presented" will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of "withdrawn" or "previously presented." Any claim added by amendment must be indicated with the status of "new" and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of "canceled" or "not entered."
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as "canceled" will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a "new" claim with a new claim number.
For the sake of compact prosecution, the claims 2, 4, 12, and 15 are being evaluated upon the interpretation that they were meant be presented as “(Currently amended)”.
Claims 1-12 are examined on the merits herein.
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 1: This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that two protein sequences, “HLLQFNKMIKFETRKNAIPF” – (Peptide A) and “AIPFYAFY” (Peptide B), appear in the specification at [055]. These peptides and sequences are included as comparative examples. However, these sequences are not in the Sequence Listing received on 05-05-2023. Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency 2: 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). The examiner has noted that two protein sequences, “HLLQFNKMIKFETRKNAIPF” – (Peptide A) and “AIPFYAFY” (Peptide B), appear in the specification at [055] without a sequence identifier.
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:
As merely a matter of form, the phrases “SEQ ID” should instead be amended to recite “SEQ ID NO: ”, to match precisely with the naming format of the Sequence Listing file.
Appropriate correction is required.
Claim Objections
Claims 4, 6, 8, 9 and 11 are objected to because of the following informalities:
The phrase “the cycle of progression” in claim 4 is not a common phrase in the art, however it is clearly used to mean “cell cycle progression”, as in [063]-[065] of the specification. Correction is recommended.
As a matter of form, the phrases “SEQ ID X”, in claims 6, 8, and 9, should instead be “SEQ ID NO:X”. Example: “SEQ ID 1” should say “SEQ ID NO:1”.
Claim 11 recites “he” in line 1, which appears to be a typo for “the”.
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 1-12 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.
Claim 1 recites a bioactive synthetic peptide “derived from the C-terminal portion of the Crotoxin B snake venom toxin.” There is no manner for one of skill in the art to determine what defines the “the C-terminal portion of the Crotoxin B snake venom toxin”. No specific sequence is recited in the claim. There is no manner for one to determine where the “C-terminal portion” begins, in comparison to the entire Crotoxin B snake venom protein. There are no limits to the length of the peptide, nor is there a specified species of the snake venom protein, from which the peptide is derived. The specification teaches that “The term "bioactive peptide(s)" comprises the C-terminal part of the crotoxin protein obtained from Crotalus durissus terrificus and its derivatives”, but this does not limit the C-terminal to any specific part. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). There is no special definition provided to limit the “the C-terminal portion of the Crotoxin B snake venom toxin” and thus one cannot determine if any particular peptide fulfills this limitation or not. Because the metes and bounds of the protection sought is unclear, the claim is indefinite. For the purposes of compact prosecution and comparing the claims to the prior art, the phrase is being interpreted as that the C-terminal portion includes the peptide sequence of MFYPDSRCRGPSET, as set forth in SEQ ID 1, and as recited in dependent claims 6-9 and in the instant embodiments.
The term “little to no toxic effect” in claim 1 (line 3) is a relative term which renders the claim indefinite. The term “little to no” 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. The instant disclosure does not set forth a specific definition for determining if “a little” toxic effect is present or not. There is no manner to determine the metes and bounds of the claimed invention, and the resulting claim is indefinite.
Claims 8, 9, and 10 each recites the limitation "the bioactive protein”. Claims 6, 7, 8, 9, 10, and 11 also recite “the bioactive peptide”. There is insufficient antecedent basis for these limitations in the claims. Claim 1 recites “A bioactive synthetic peptide”. Thus, the references to “the bioactive protein” and “the bioactive peptide” lack antecedent basis because it is unclear if these are the same as the “bioactive synthetic peptide” as recited in claim 1. This indefiniteness could be addressed by amending all the references to say “bioactive synthetic peptide”.
Claim 7 recites “wherein the bioactive peptide has a purity of between 70% to greater than 95%”. This range is considered indefinite because the limitation does not clearly set forth the metes and bounds of the patent protection desired. The claim recites “between 70% to greater than 95%”. Under the plain meaning of the terms, the claim means that the purity is at least 70%, or greater than 95%. It is noted that this is not the same as “between 70% to 95%”. Under one interpretation, the recitation of “greater than 95%” is a narrower statement of the range (i.e. that of 95% to 100%). The claim is 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 12 recites “administered in vivo or in”, without finishing the claim, nor including a period. MPEP § 608.01(m) states that “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.” Claim 12 appears to be unduly truncated and there is no period. Thus, the full scope of the claim cannot be determined. For the purposes of compact prosecution, the phase is herein interpreted to be “administered in vivo or in vitro.”, as presented in the originally-filed claims.
All other claims depend directly or indirectly from the rejected claims and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
Claim Rejections - 35 USC § 112(a) - 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 1-5 and 11-12 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 claims 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.
Claim 1 recites: a bioactive synthetic peptide derived from the C-terminal portion of the Crotoxin B snake venom toxin having anti-tumoral activity against aggressive solid tumors and little to no toxic effect over benign cells. The full scope of the claim is thus drawn to any bioactive peptide derived from “the C-terminal portion of the Crotoxin B snake venom toxin”.
The dependent claims 2-5 and 11-12 do not practically limit the encompassed peptides to only those sequences disclosed in the instant application as having the claimed functionalities.
Claims 6 and 7 limit the bioactive synthetic peptide to those having the amino acid of SEQ ID NOs:1-10 (or combinations thereof). Claim 8 recites that the peptide has at least 70% similarity to one of SEQ ID NOs:1-10 (and the functional properties required thereof). Claims 9 and 10 limit the bioactive protein to comprising the amino acid sequence of SEQ ID NO:1.
Claims 1-5 and 11-12 thus encompass any and all peptides “derived from the C-terminal portion of the Crotoxin B snake venom toxin” and having the claimed bioactive functions. Because a protein’s functions are intrinsically linked by the amino acid sequence, the sequence and structure are what defines the properties and activity of the claimed peptide.
According to the B.R.I. of the claim, when viewed in light of the specification, there exists a nearly limitless number of peptide structures and sequences within the claimed scope. These include any and all peptides that can be “derived from” the C-terminal half of the Crotoxin B snake venom toxin from Crotalus durissus terrificus, a basic, toxic phospholipase A2 (PLA2) also known as Component B or CB (see [009] of the specification). This includes potential mutations, derivatives and fragements thereof, without any specified length or structure.
Comparatively, the specification only recites a small number of species of the broad genus that meets the recited limitations.
MPEP § 2163.(II)(A)(3)(a) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. The instant specification fails to reasonably describe the full genus of the claimed invention by providing identifying characteristics or functional properties of the claimed peptide, such that one can predict which sequences fulfill the claimed functions and which will lack the activities.
Further, the instant specification does not disclose relevant identifying characteristics, such as key structural or other physical properties, or functional characteristics coupled with a known or disclosed correlation between function and structure, such that the entirety of the claimed genus is encompassed by the description in the disclosure. The specification teaches generally that peptides having a sequence of, or highly similar to, SEQ ID NO:1 (named 3-NantC herein) will fulfill the claimed activities of having anti-tumoral activity against aggressive solid tumors and no (or “little”) toxic effect on benign cells. However this is a description of a single embodiment of the claimed genus, and there is no known or disclosed relationship between the sequence and function that is sufficient to fulfill the written description requirement.
The examples in the specification include the peptide 3-NantC, having the sequence of SEQ ID NO: 1 (see Examples and [051]-[076]; Figures 3-12), which was tested for efficacy against triple negative breast cancer cells (MDAMB231), as well as toxicity towards benign cells (fibroblasts -HDFa cells). Peptides according to SEQ ID NOs: 2-10 were also tested for cancer cell inhibition, as shown in Figs. 13 and 14, yet no data against benign cells is presented ([077]).
Thus, the specification only provides only one example of the claimed genus which fulfills both the cancer cell activity and has “little to no toxicity” against benign cells, which cannot be considered a sufficient description of a representative number of species by actual reduction to practice of the full breadth of the vast genus. There is no evidence that, at the time of filing, the Applicant possessed additional representative species of the full genus recited in the claims beyond that of 3-NantC and its disclosed derivatives (SEQ ID NOs: 1-10), as provided in the working examples.
For these reasons, the disclosure fails to provide adequate written description to support the entirety of the broad genus claim to any and all “bioactive” peptides derived from the C-terminal half of the Crotoxin B snake venom toxin.
Claim 1 is thus rejected under 35 U.S.C. § 112(a) because the claimed subject matter is not described in the specification in such a way as to reasonably convey to a skilled artisan that the inventor, or a joint inventor, had possession of the claimed invention. The dependent claims 2-5 and 11-12 are also rejected under 35 U.S.C. § 112(a), because these claims require directly or indirectly the bioactive synthetic peptide, according to claim 1 and fail to practically further limit the claimed invention to only that which is adequately described in the disclosure as filed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
For determining subject matter eligibility, the following analysis was considered, per MPEP § 2106.
Patent Eligibility Analysis Step 1: Step 1 of the eligibility analysis asks: is the claim to a process, machine, manufacture or composition of matter? Yes, the claims are directed to a composition. (Claims 1-12, STEP 1: YES).
Patent Eligibility Analysis Step 2A Prong 1: Step 2A, prong 1 asks: does the claim recite an abstract idea, law of nature, or a natural phenomenon (product of nature)?
Claim 1 recites a bioactive synthetic peptide derived from the C-terminal portion of the Crotoxin B snake venom toxin. Although the claims state that peptide is synthetic, the sequence, structure, and thus functions of the peptide and fragments thereof amount to a naturally occurring peptide or a fragment thereof, derived from a natural source. Claims 2-5 and 11-12 recite the peptide of claim 1 encompassing the natural sequence and functional properties thereof. The claims do not limit the size of the derived peptide to any particular fragment size.
Claims 6-10 further limit the peptide to those comprising specific sequences, including a sequence SEQ ID NO:1 derived from a natural protein. SEQ ID NO:1 comprises a sequence that is 100% identical to a portion of CTX subunit CBd from Crotalus durissus terrificus, as described in the specification ([042]) and evidenced from NCBI Entry C0HM14 (“Phospholipase A2 crotoxin basic subunit CBd”, NCBI, provided with PTO-892).
All of claims 1-12 encompass the embodiment of the invention wherein the bioactive protein comprises SEQ ID 1, which is a fragment of a naturally-occurring peptide sequence.
Thus, the B.R.I. of claims 1-12 includes limitations encompassing natural products.
When a claim recites a nature-based product limitation, the markedly different characteristics (MDC) analysis is used to determine whether the natural product has markedly different characteristics from its natural counterpart (see MPEP 2106.04(c)). MPEP § 2106.04(c) explains “Where the claim is to a nature-based product produced by combining multiple components, the markedly different characteristics analysis should be applied to the resultant nature-based combination, rather than its component parts.”
In this case, the appropriate natural counterpart for the “bioactive synthetic peptide” of claims 1-12 would be at least one of the natural occurring polypeptides containing the sequence of SEQ ID NO:1. The instantly claimed peptide encompasses peptide sequences identical to naturally-occurring peptides.
The second step in the MDC analysis is to identify appropriate characteristics to compare. Appropriate characteristics can be expressed as the nature-based product’s structure, function, and/or other properties, and are evaluated on a case-by-case basis. In this case, the appropriate characteristics include: biological functions or activities including the anti-tumor, apoptosis-inducing, and anti-cell proliferation effects as described in the instant specification, and characteristics of sequence, structure and form (e.g. the chemical, genetic or physical attributes) of the natural component. The final step in the markedly different characteristics analysis is to compare the characteristics of the claimed nature-based product to its naturally-occurring counterpart in its natural state, in order to determine whether the characteristics of the claimed product are markedly different. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally-occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP § 2016.04(c).II.C.). If there is no change in any characteristic, the claimed product lacks markedly different characteristics, and is a product of nature exception.
The instant specification describes that the naturally-derived peptide, having a sequence that is completely unchanged compared to the natural sequence, has the properties of affecting cellular proliferation, apoptosis, necrosis and cycle progression in tumor cells, while not being toxic against benign cells ([010]-[014]; [043] of the specification). Further, the peptide (that of the invention and identical to a natural sequence of amino acids, i.e. a fragment) causes a marked difficulty of tumoral cells to proceed to GO/G1 stage, while leads to an arrest in both S and G2/M phases, according to the instant specification ([043]).
No characteristics of the naturally-derived peptide (i.e. fragment) comprising at least the naturally occurring SEQ ID NO:1, are found markedly changed compared to a naturally occurring counterpart fragment. Although the instant specification describes that “the C-terminal of the Crotoxin B and its derivatives have a lessened toxic effect” against benign cells and “an elevated anti-tumoral activity against tumor cells but specifically against triple-negative breast cancer cells”, these are not due to any intervention or transformation of the peptide, but are instead merely the discovery and characterization of a naturally-occurring peptide sequence and intrinsic, or innate, characteristics thereof.
The specification ([010]) states that “It is known from the state of art that the crotoxin protein contains different molecular regions responsible for specific pharmacological activities - neurotoxicity, myocity, nephrotoxicity and cardiotoxicity are the most common activities of this protein in vivo... the exact location of the active sites in the structure of the snake venom responsible for its toxic activity remained unclear, being attributed to the N-terminal, IBS (interfacial binding surface) or C-terminal in different independent international studies.” However, the discovery of a natural but unappreciated property does not differentiate the invention from it’s naturally-occurring counterpart.
See MPEP § 2106.04.I., which states that “The Supreme Court’s cited rationale for considering even "just discovered" judicial exceptions as exceptions stems from the concern that "without this exception, there would be considerable danger that the grant of patents would ‘tie up’ the use of such tools and thereby ‘inhibit future innovation premised upon them.’" Myriad, 569 U.S. at 589, 106 USPQ2d at 1978-79 (quoting Mayo, 566 U.S. at 86, 101 USPQ2d at 1971). See also Myriad, 569 U.S. at 591, 106 USPQ2d at 1979 ("Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the §101 inquiry.")”.
When considered as a whole, there is no evidence or suggestion that the claimed “bioactive synthetic” peptide has any markedly different characteristic than a naturally occurring peptide fragment comprising the claimed sequence. Further, it is noted that the claims are comprising-type claims and do not necessary preclude the presence of additional amino acid. Fragmentation of proteins is a natural process and thus, any differences of a full length protein compared to a fragment thereof are likewise, naturally-occurring phenomenon. See MPEP § 2106.04(c).II.B and II.C.2, which describes that not all changes in characteristics will rise to the level of a marked difference: “In Ambry Genetics, the court identified claimed DNA fragments known as "primers" as products of nature, because they lacked markedly different characteristics. University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014).” and “a similar result was reached in Marden, where the court held a claim to ductile vanadium ineligible, because the "ductility or malleability of vanadium is . . . one of its inherent characteristics and not a characteristic given to it by virtue of a new combination with other materials or which characteristic is brought about by some chemical reaction or agency which changes its inherent characteristics". In re Marden, 47 F.2d 958, 959, 18 CCPA 1057, 1060, 8 USPQ 347, 349 (CCPA 1931)”.
Therefore, because the claimed peptide lacks any markedly different characteristics, the claims recite a product of nature exception (Claims 1-12, Step 2A, Prong 1: YES).
Patent Eligibility Analysis Step 2A Prong 2: Step 2A, prong 2 asks: does the claim recite additional elements that integrate the judicial exception into a practical application?
Claim 1 does not recite any additional elements other than the product of nature exception, specific limitations regarding the natural components, and functional limitations thereof, such as “having anti-tumoral activity against aggressive solid tumors and little to no toxic effect over benign cells.” These functional limitations regard intended uses and not practical applications of the judicial exception. Claims 6-9 recite specific sequences, which all include the naturally occurring sequence of SEQ ID NO:1, as explained above. Further, claim 7 recites that “the bioactive peptide has a purity of between 70% to greater than 95%” but this does not amount to a practical application of the peptide, it is merely a limitation regarding the isolation effectiveness. The peptide is not changed and there is no particular requirement or method by which the purity is obtained or measured.
Claims 2-5 and 10 further limit the intended uses (e.g. targeting specific cancer types) and functional characteristics of the peptide (e.g. having effects on the “modulation of cellular proliferation, apoptosis, necrosis, the cycle of progression and any combinations thereof”), but it is evident that these are intrinsic properties of a naturally occurring peptide sequence.
Claim 11 recites a composition comprising the bioactive peptide in a “pharmaceutically acceptable vehicle as a carrier, a diluent and/or an excipient”, which is not defined further in the specification. Thus, the pharmaceutically acceptable carrier could comprise any suitable natural substance, such as water or a buffering solution. This doesn’t differentiate the claims from the natural product, nor does it recite a practical application thereof. It merely recites that the natural product is combined with what amounts to another natural products (e.g. water, glycerol, sucrose, et cetera).
Claim 12 recites that the composition is administered, but this is at a high level of generality, not amounting to a practical application. The claim does not recite any concenrations nor does it limit the subject population to be administered to. As an example only, the claim may be amended to recite that the composition is administered in a therapeutically effective amount for the treatment of a solid tumor when the tumor is a triple negative breast cancer, as disclosed by the specification ([022]).
There is no practical application or implementation of the natural product required by claims 1-12. Thus, the judicial exception is not integrated into a practical application because the claims do not recite any additional elements other than the naturally-occurring products, innate functional characteristics, or intended uses thereof (Claims 1-12, Step 2A, Prong 2: NO).
Patent Eligibility Analysis Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
The recitation of an innate property, activity, or characteristic of a naturally occurring peptide does not result in significantly more than the judicial exception. The recitations of tumor-treating activity in claim 1 amounts to functional language regarding intrinsic characteristics and intended uses, not to structural limitations of the claimed peptide. From the specification, and the data in the Figures, it is evident that the naturally occurring sequence of SEQ ID NO:1 possesses these innate characteristics.
Claims 2-5 and 10 recite additional elements which do not practically limit the claims to anything other than the natural products, instead these merely recite specific elements or functional properties of the product and not any specific structural limitations. The natural sequence of SEQ ID NO:1 has been shown to have these properties.
Further, none of the additional elements recited in claims 6-10 amount to significantly more than the ineligible natural product, when considered as a whole. The purification requirements of claim 7 do not cause any particular transformation or practical implementation of the natural peptide, and peptide isolation and purification is standard in the field.
For claims 11 and 12, the pharmaceutically acceptable vehicle as a carrier encompasses naturally occurring solvents such as water, which is itself a natural product, and thus is not considered an additional element that amounts to significantly more than the ineligible natural product. The high general recitation of “administered in vivo” in claim 12 does not amount to significantly more than the natural product and a general instruction to use it. As explained above, there is no specific application, concentration, nor limitation of the intended subject population to receive the treatment.
When considered individual or in combination, the claims do not amount to more than the judicial exception.
Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (Claims 1-12, Step 2B: NO).
As such, the claims do not qualify as eligible subject matter. For these reasons, claims 1-12 are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Odolczyk (US PGPub No. 20190391160).
Odolczyk discloses peptide modulators for treating cystic fibrosis that comprise or consist of an amino acid fragment of the CB subunit of crotoxin from Crotalus durrissus terrificus venom, which is substantially the same as the claimed peptides herein (Abstract, Title).
Odolczyk discloses that the peptide modulator may comprise or consist of the amino acid sequence of SEQ ID NOS: 1, 2, 3, 4, 5 or 6, as disclosed therein. It is noted that SEQ ID NO: 4 of Odolczyk is NGYMFYPDSRCRG, which is 74.1 % identical to that of the instant SEQ ID NO:1. Further, SEQ ID NO:4 of Odolczyk comprises a sequence that is 100% identical to that of SEQ ID NO:4 (MFYPDSR) in the instant claims. The sequence is also greater than 70% similar to that of SEQ ID NOs: 6 and 7 in the instant application.
Odolczyk states that the peptide modulator can comprise “a polypeptide comprising the amino acid sequence NGYMFYPDSRCRG (SEQ ID NO: 4); a polypeptide consisting of the amino acid sequence SEQ ID NO: 4, and a polypeptide comprising a functional variant of SEQ ID NO: 4” ([0006]; [0048]; claim 26). Odolczyk states that the peptide NG-13(105-117) having the sequence of SEQ ID NO: 4 was soluble and able to bind the intended target ([0140]) and this peptide is found at the C-terminal end of the CBb protein (see Fig. 18).
Odolczyk also states that “In some embodiments the peptide modulator is synthetic. In some embodiments the peptide modulator is isolated. In some embodiments the peptide modulator is purified.”, thus disclosing a purified synthetic peptide.
Thus, Odolczyk discloses a bioactive synthetic peptide derived from the C-terminal portion of the Crotoxin B snake venom toxin, having an amino acid sequence comprising all of SEQ ID NO:4, and having at least 70% identity to that of SEQ ID NOs 1 and 6, fulfilling all of the structural limitations of claims 1-8.
Regarding claim 7, Odolcyzk discloses that the peptide modulator is purified, and although no specific numbers are presented, purity in the art of recombinant peptides and biochemistry especially among synthetic peptides as disclosed in [0051] of Odolcyzk would inherently be predictably greater than 95% as claimed. Further, the purification of the snake Crotoxin component B is well-known in the art, as evidenced in the instant specification at [008]-[009], and further evidenced by the reference Faure, G and C Bon. 1988 (“Crotoxin, a phospholipase A2 neurotoxin from the South American rattlesnake Crotalus durissus terrificus: purification of several isoforms and comparison of their molecular structure and of their biological activities.” Biochemistry vol. 27,2 (1988): 730-8), which was incorporated by reference in Odolcyzk ([0032]: “Certain references and other documents cited herein are expressly incorporated herein by reference”; and [0085]).
Odolczyk is silent regarding the anti-tumoral activity against aggressive solid tumors and little to no toxic effect over benign cells of this specific peptide. Odolczyk is also silent in regards to the further functional limitations of claims 2-5.
However, the disclosed peptide fragment corresponding to SEQ ID NO:4 in Odolczyk comprises all of the sequence of the instantly claimed SEQ ID NO:4 and fulfills the structural requirements of being at least 70% identical to SEQ ID NO:1 or 6. SEQ ID NO:4 contains anti-tumoral activity, as evidenced in the data of Fig. 13. Because the instant claims encompass the sequence of Odolczyk, the claimed properties and functions thereof are presumed to also be inherently present in the sequence fragment of this prior art.
MPEP § 2112.01 establishes that when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent; “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).”.
In the instant case, the peptide of Odolczyk comprising a structure which is identical or nearly identical to multiple embodiments of the invention, is deemed to inherently possess the claimed functional properties of anti-tumor activity and lack of toxicity towards benign cells.
Further, the peptide of Odolczyk fulfills one or more of the sequence/structural limitations in claims 6-8. The purity requirements of claim 7 are deemed anticipated by the disclosure of Odolczyk for the reasons discussed above
In regards to claims 2-3, the selection of a suitable tumor which the activity is targeted amounts to nothing more than an intended use, and thus, the intrinsic functions of the peptide, being the same as that so instantly claimed, would also anticipates these intended uses.
Regarding claims 4-5, these limitations amount to further functional properties, which are evidently present in the peptides according to the claims, as demonstrated by the instant specification, and thus, the prior art peptide of Odolczyk also inherently anticipates claims 4-5.
In the alternative, even if the composition (with respect to the structure of the peptide fragments) is not completely identical to the referenced composition and effects, with regard to some unidentified characteristics, the differences between that which is claimed and that which is disclosed, is so slight that the referenced composition is likely to inherently possess the same characteristics of the claimed composition, particularly in view of the similar characteristics which they have been shown to share and by the functions of the component materials (i.e. the same sequence leading to the same peptide features and biological activities) inherently present in each and which functions are inclusive of those appreciated in the instant disclosure as being present (see MPEP 2112.02 at Ex parte Novitski, in reference to reference-silent functioning of biological materials providing anticipation of the functions based upon the material itself- noting the reference of “Dart” therein did not appreciate the claimed function but still anticipated the function based on the inherent function of the material, and that the Applicant’s disclosure appreciating the function upon usage thereof as further evidence of the presence of the function).
Thus, the claimed composition comprising a bioactive synthetic peptide derived from the C-terminal portion of the Crotoxin B snake venom, and the therapeutic effects upon administration thereof, would have been anticipated, or in the alternative, at least obvious to those of ordinary skill in the art within the meaning of 35 USC § 103(a).
The dependent claims are found obvious for at least all of the reasons thereof. Further, even if minor structural or concentration differences exist, optimization of the peptide sequences and applications thereof would amount to nothing more than routine experimentation for tailoring the peptide for the desired results according to known guidance in the art.
From the teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the references, especially in the absence of evidence to the contrary.
Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the disclosure and peptide of Odolczyk, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Please note, since the Office does not have the facilities for examining and comparing Applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Claim Rejections - 35 USC § 103
The text of the relevant sections of Title 35, U.S. Code can be found above.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Almeida et al. (2021, “The anti-cancer potential of crotoxin in estrogen receptor-positive breast cancer: its effects and mechanisms of action.” Toxicon 200, pgs. 69-77, on IDS filed 5/2/2024) in view of Yount et al. (US PGPub 20200165309, on IDS filed 5/2/2024) and Gopalakrishnakone et al. (PGPub US 20070128179 A1).
Almeida pertains to the study of the anti-cancer effects of crotoxin B (referred to as CTX) in an ER + aromatase-overexpressing breast cancer cell line (Title, Abstract).
Almeida teaches that CTX impairs cancer cells growth through a cell cycle arrest at G 2 /M phase, inhibition of ERK1/2 pathway and by apoptosis through activation of caspase-8 and that it can be considered a safe natural compound as did not affect non-cancerous cells and only showed anti-growth effects in breast cancer cells (Abstract).
Almeida teaches that it was previously known in the art that PLA2 toxins have anti-cancer properties in vitro and in vivo, being involved in the inhibition of angiogenesis, migration and adhesion of cancer cells, such as carcinoma cervical cells, human breast cancer cells and human lung squamous cells (pg. 70, left col). Almeida teaches that crotoxin B is derived from venom of the South American rattlesnake Crotalus durissus terrificus and has recognized anti-tumoral effects in several types of cancer, including ovary carcinoma, melanoma, leukemia, breast cancer, lung cancer, glioma, cervix cancer, colon cancer, renal cancer, pancreatic cancer, esophageal cancer and cervical cancer (pg. 70, left col). Almeida teaches that the CTX (Crotoxin B) polypeptide was purified via molecular exclusion and reverse phase high performance liquid chromatography, and the prepared in the vehicle DMSO (pg. 70, right col, last paragraph).
Thus, Almeida teaches a peptide comprising the Crotoxin B snake venom toxin, including the C-terminus, and having anti-tumoral activity against tumor cells (e.g. MCF-7aro cells that express high levels of the aromatase enzyme with added testosterone which promotes solid tumor progression, e.g. a model of aggressive breast cancer tumors, see pg. 70, right col.) and little to no toxic effect over benign cells (see Fig. 1 and sections 3.1 and 3.2 on pg. 72).
Regarding claim 2 and 3, these claim limitations are drawn to functional applications of the peptide, however Almeida teaches that the Crotoxin B protein has recognized activity against a variety of cancer types, and teaches using the protein against ER+ breast cancer cells (pg. 70).
Regarding claims 4 and 5, Almeida teaches that Crotoxin B has anti-cell proliferation activity and increased the number of cells in the G2/M phase while also causing a significant decrease of cells proceeding to S phase, which is the same as instantly claimed, wherein there is difficult in proceeding through the G0/G1 phase into S phase and there is simultaneously an arrest at the G2/M phase (pg. 72, section 3.2; Table 1; and also see pg. 74 left col, last paragraph). Almeida also teaches that the toxin promoted apoptotic cell death in MCF-7aro cells (pg. 73, section 3.3 and Fig. 2).
Regarding claim 10, Almeida teaches that CTX did not involve autophagy as a cell death mechanism (pg. 74, right col, 2nd paragraph; Table 3).
However, Almeida does not teach that the peptide used is “derived from” the C-terminus of Crotoxin B, nor that it is one of the peptide fragments such as SEQ ID NOs:1-10 as recited in the instant claims (or limited to SEQ ID NO:1 as in claims 9-10).
Yount teaches a variety of α-helical antimicrobial peptides and administering to a patient an effective amount of a composition comprising an α-helical antimicrobial peptide (Abstract). The peptides in Yount include one (SEQ ID NO:2395) that is 36 amino acids in length and comprising a sequence having 100% identity to that of the instantly claimed peptide SEQ ID NO:1 (see alignment below). SEQ ID NO:2395 in Yount is clearly derived from the C-terminus of Crotoxin B, as it ends in the same sequence so instantly claimed. Thus, fragments having only portions of the Crotoxin B C-terminal are known in the art for therapeutic uses.
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Gopalakrishnakone teaches phospholipases - including isoforms, derivatives, mutants and/or fragments thereof- that may be obtained from, inter alia, at least the venom of Crotalus durissus terrificus (Abstract). Gopalakrishnakone teaches that the phospholipase, isoform, derivative, mutant and/or fragment thereof may be comprised as a pharmaceutical composition in conjunction with at least one pharmaceutically acceptable excipient, diluent, carrier and/or adjuvant in a form suitable for administration to a subject ([0101; claim 14).
The peptides of Gopalakrishnakone include crotoxin B from Crotalus durissus terrificus ([0146], Figure 7(f)) and Gopalakrishnakone teaches that crotoxin B displays strong antibacterial activity against various bacteria ([0160]). The reference teaches that the purified PLA2s, including crotoxin B, did not change the viability (FIG. 7f-g) of cells up to 0.05-10 µg/mL concentrations as compared to the control ([0169]; Fig. 7, Fig. 9).
Gopalakrishnakone teaches that the C-terminal segment of crotoxin B has interesting properties that are suggested to account for its strong antimicrobial activities, thus indicating a possible active site that contributes to the unique qualities of crotoxin B ([0175]: “the C-terminal segment of crotoxin B, on the other hand, shows a modest difference in the amino acid residues as compared with the C-terminal sequences of other venom PLA.sub.2s. Moreover, comparison of the hydropathic profiles of different snake venom PLA.sub.2s reveals that the C-terminal segment of crotoxin B is relatively more hydrophobic than those of other PLA.sub.2s (FIG. 15). This cationic hydrophobic nature of crotoxin B phospholipase A.sub.2 enzyme may most likely be responsible for the strong antimicrobial action seen on B. pseudomallei”).
Therefore, prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to arrive at a crotoxin B-derived peptide having anti-tumor properties, including the one of Yount comprising a C-terminal fragment of SEQ ID NO:1, because Almeida teaches that crotoxin B (CTX) is known for anti-tumor properties including induction of apoptosis and inhibition of cancer cell proliferation and Yount teaches that bioactive C-terminal fragments of CTX comprising the C-terminal fragment of SEQ ID NO:1 are known in the art while Gopalakrishnakone teaches there exists functional activities attributed to the CTX C-terminus; and further the peptide would predictably have minor effects on benign cells as suggested by the combined teachings of Almeida and Gopalakrishnakone.
One having ordinary skill in the art of producing peptides for cancer treatments would recognize that blocking proliferation selectively targets over-proliferative cancer cells and not benign cells. Further, the combined teachings of Almeida and Gopalakrishnakone would suggest that the toxin or fragments thereof, administered in appropriate doses, would have less effect on healthy cells than on the undesirable cells (i.e. the cancer cells targeted in Almeida or the pathogen cells targeted in Gopalakrishnakone). Although Almeida teaches the anti-proliferative and apoptosis-inducing effects of the full length crotoxin B, the sequence of the full length protein includes the claimed sequence of SEQ ID NO:1 (NCBI Entry C0HM14, cited on the accompanying PTO-982).
Further, the selection of peptide fragments, including the peptide of SEQ ID NO: 2395 disclosed as having useful bioactivity in Yount and clearly from the C-terminal of crotoxin B, would have been obvious among fragments to test or use for anti-tumor activity, because Gopalakrishnakone teaches there is a recognized hydrophobic binding region in the C-terminus of crotoxin B, and thus one having ordinary skill in the art would have been motivated to test such a fragment. See MPEP § 2143.I.G describing that a solution is obvious when a teaching, suggestion, or motivation (TSM) in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, as discussed above.
Further, the discovery of useful fragments from among the wild-type sequence already known to the art would have been a matter of routine optimization and assaying to one of ordinary skill in the art. See MPEP § 2143.I.E. describing that a solution is "obvious to try" – when one of ordinary skill chooses from a finite number of identified, predictable solutions, with a reasonable expectation of success, which in this case pertains to the known possible peptide sequences of crotoxin B, including the known active sites, recognized areas of conservation, and known interesting features of fragments, such as the hydrophobicity of the C-terminus taught in Gopalakrishnakone. Thus, it would have been predictable, with a reasonable expectation of success, for one having ordinary skill in the art to test different fragments of the crotoxin B peptide used in Almeida, including using the C-terminus region taught in Yount, to arrive at a peptide fragment according to the instant invention, derived from the C-terminus region and possessing the claimed improved functions.
The functional limitations of claims 2-5 would likewise been obvious over the combined teachings of Almeida, Gopalakrishnakone, and Yount, as Almeida teaches that a sequence comprising at least all of SEQ ID NO:1 has the recited properties. Thus, if one was to experiment and arrive at the C-terminus fragment, such as the one taught in Yount, then these properties would also inherently be present (and which functions are inclusive of those appreciated in the instant disclosure as being present - see MPEP 2112.02 at Ex parte Novitski, in reference to reference-silent functioning of biological materials providing anticipation of the functions based upon the material itself, noting the reference of “Dart” therein did not appreciate the claimed function but still anticipated the function based on the inherent function of the material, and that the Applicant’s disclosure appreciating the function upon usage thereof as further evidence of the presence of the function).
Regarding claim 3, although effects against triple negative breast cancer are not taught explicitly in Almeida, the claim does not actually require any administration of the peptide, just that the peptide has the useful activity (i.e. functional property and intended use) if that cancer is selected for the treatment. Because Almeida teaches specific activity of crotoxin against a related breast cancer, and because it also discloses that the peptide has known therapeutic uses in many types of cancer, including ovary carcinoma, melanoma, leukemia, breast cancer, lung cancer, glioma, cervix cancer, colon cancer, renal cancer, pancreatic cancer, esophageal cancer and cervical cancer, it would have been obvious to provide the peptide for these tumor subtypes.
Regarding claims 6-9, the peptide fragment taught in Yount comprises the entire sequence of SEQ ID NO:1 and thus, the selection of at least one alterative limitation in these claims would be prima facie obvious in view of the cited art, for the reasons discussed above.
Regarding claim 7, Almeida teaches that the CTX (Crotoxin B) polypeptide was purified via molecular exclusion and reverse phase high performance liquid chromatography, which are well-known in the art, and thus, the purification of any useful peptide to a high degree of purity would have been obvious and a matter of routine optimization and procedure to one of ordinary skill in the art.
Claim 10 further recites that the “bioactive protein anti-tumoral activity does not include the promotion of autophagy”, which is clearly taught in Almeida as described above. Thus, it would have been predictable that using the sequence comprising SEQ ID NO:1, such as the peptide taught in Yount, would also not have this described activity.
Regarding claims 11 and 12, Gopalakrishnakone teaches that the phospholipase, isoform, derivative, mutant and/or fragment used therein may be comprised as a pharmaceutical composition in conjunction with at least one pharmaceutically acceptable excipient, diluent, carrier and/or adjuvant in a form suitable for administration to a subject. Almeida teaches that the crotoxin B peptide is prepared in DMSO, which is a common vehicle/solvent in the art. Further, one of ordinary skill in the art would be knowledgeable in the preparation of compositions with bioactive components and pharmaceutically acceptable vehicles, and thus providing the bioactive peptide in this manner, intended for use in vivo for delivering to a patient in need thereof, would have been prima facie obvious in view of the cited art.
From the teachings of the cited references, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because each of the references pertain to at least a sequence comprising that of SEQ ID NO:1 and its bioactive uses, and Almeida discloses that crotoxin B has anti-tumor properties useful for reducing the viability of aggressive solid tumor cells.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of convincing evidence to the contrary.
Citation of Pertinent Art
The following relevant art made of record and not relied upon is considered pertinent to applicant's disclosure.
Olórtegui et al., BR102020024827, discloses a vaccine composition against Crotalus snakebites, using epitopes from crotoxin B, and teaches the C-terminal peptide fragment 103-YKNGYMFYPDSRCRGPSETC-122, which contains a sequence that is 100% identical to that of SEQ ID NO:1 in the instant application (see [019] of the provided translation). The publication date of the foreign application is 6/14/2022, later than the instant effective filing date.
Bezerra, et al. (“3-NAntC: A Potent Crotoxin B-Derived Peptide against the Triple-Negative MDA-MB-231 Breast Cancer Cell Line”. Molecules 2024, 29, 1646) is a research article authored by the inventors of the instant application which discloses the instant invention, but is not qualified as prior art. The reference is made of record herein for evidentiary purposes.
Conclusion
No claims are allowed.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655