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
Applicant’s election without traverse of Group I, claims 1-15 and 28, and the species SEQ ID NO: 1, which reads on claims 1-4, 6-10, 13-15 and 28, in the reply filed on February 26, 2026, is acknowledged.
Claims 16-27 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 5 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The specification ([11]) states that the application file contains at least one drawing executed in color. However, there is no drawing in color nor is there a petition.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
BRI of the claim term “membrane-active” includes but is not limited to blood-brain barrier opening. 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).
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.
Claims 1-4, 6-10, 13-15, and 28 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 blood-brain barrier opening with Melittin-COO- (SEQ ID NO: 2), Melittin-CONH2 (SEQ ID NO: 1), MelP3 (SEQ ID NO: 5), and MelP5 (SEQ ID NO: 7) (Table 2) for the delivery of dextran, does not reasonably provide enablement for the full scope of Formula I for blood-brain barrier opening for the delivery of all therapeutic and diagnostic agents. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The invention is in the unpredictable field of peptides useful for opening the blood-brain barrier and delivering therapeutic and diagnostic agents to the brain (specification, para. [04]).
The Breadth of the Claims
The genus of membrane-active peptides of Formula (I) includes an infinite number of amino acid sequences owing to the broad definition of amino acids at each of the 26 positions.
The genus of therapeutic and diagnostic agents is also exceptionally broad and encompasses small molecules, proteins, peptides, antibodies, nucleic acids and other structures with any therapeutic or diagnostic function.
The State of the Prior Art
The prior art of WO 2012/083185 A1 discloses a composition for delivering an RNA interference polynucleotide (RNA-i) to a liver cell in vivo comprising a melittin delivery peptide and an RNA-i (page 4, lines 18-24). The melittin peptide may have the sequence GIGAVLKVLATGLPALISWIKRKRQQ (SEQ ID NO: 80, Figure 1) and may contain an amide at the C-terminus (page 6, line 7), corresponding to the elected species SEQ ID NO: 1.
Although the composition taught by WO 2012/083185 A1 falls within the scope of the instant product claims, it does not disclose the blood-brain barrier opening ability reported in the instant specification.
The Predictability or Unpredictability of the Art
The prior art pertaining to the opening of the blood-brain barrier and delivery of therapeutic and diagnostic agents to the brain is highly unpredictable. See specification at para. [05]-[10] as well as NPL3-NPL5 cited by Applicant on the IDS filed 4/30/2024.
The Level of Guidance in the Specification
The level of guidance in the specification is insufficient to determine which of the countless species encompassed by the claim can be used for blood-brain opening. Although the specification asserts a general correlation between structure and function for the claimed genus, the assertion is based on the analysis of four closely related peptides (Table 2). The role of the 26 amino acids of Formula I in are not adequately described.
The Presence or Absence of Working Examples
The specification discloses the actual reduction to practice of Melittin-COO- (SEQ ID NO: 2), Melittin-CONH2 (SEQ ID NO: 1), MelP3 (SEQ ID NO: 5), and MelP5 (SEQ ID NO: 7) (Table 2). Example 2 shows that melittin causes blood-brain barrier opening (BBBO) at a dose significantly below its solubility limit (1 mm versus 350 mm) (para. [188]) and that BBBO is reversible (para. [189]-[203]). The specification further discloses mechanistic studies and melittin-induced BBBO in vivo (Examples 2G-2H). Only dextran is reduced to practice as an agent that can be delivered to the brain. These species of membrane-active peptides are not representative of the full scope of the claimed genus because they are closely related compared to Formula I which includes countless amino acid sequences. In addition, dextran with structure, charge, and size properties that are not representative of the full scope of therapeutic and diagnostic agents which includes all protein, peptide, nucleic acid, and small molecule agents.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed membrane-active peptides of Formula I would be effective at BBBO. The skilled artisan would be burdened with testing a broad range of peptides in in vitro assays. The active peptides would then have to be subjected to animal models of BBBO. Any functional peptides would then need to be tested in combination with therapeutic and diagnostic agents. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
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 1-4, 6-10, 13-15, and 28 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.
In claim 1, the indefinite language is “combination”. The language is indefinite because “combination” is a relative term which renders the claim indefinite. The term “combination” 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. There is no clear metes or bounds for determining whether a given membrane-active peptide and a therapeutic and/or diagnostic agent are a combination or merely two separate products.
The dependent claims fail to remedy this issue and are likewise rejected.
Furthermore, in claims 2-4 and 6-9, the indefinite language is “non-natural analog thereof”. The language is indefinite because “non-natural analog thereof” is a relative term which renders the claim indefinite. The term “non-natural analog thereof” 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. There is no clear metes or bounds for determining whether a structure is a non-natural analog of a particular amino acid or a different structure altogether. It is not clear to what extent an amino acid can be modified or altered and still be considered a non-natural analog.
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 1-4, 6-10, 13-15, and 28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
BRI of the claims is a composition or combination of melittin peptide and a therapeutic and/or diagnostic agent. The scope of the term “combination” includes mixtures of these two components as well as separate containers for the individual components intended to be used together.
Step 1: The claims are to a composition of matter.
Step 2A, Prong 1: The claims are directed to a product of nature, the peptide melittin, in combination with a therapeutic and/or diagnostic agent. The second component, the therapeutic and/or diagnostic agent, may also be a nature-based product such as a therapeutic peptide (e.g. insulin, GLP-1), an antibody, or a small molecule (e.g. penicillin, paclitaxel, vinblastine). Because the melittin peptide and therapeutic and/or diagnostic agent as claimed are not found together in nature, the closest counterpart to the nature-based products is the individual melittin peptide and therapeutic and/or diagnostic agent.
The closest counterpart to the nature-based product therapeutic and/or diagnostic agent is that found in nature (e.g. paclitaxel from the Pacific yew tree). The claimed agent is structurally identical to the natural agent. Although the claimed agent may be isolated, there is no marked difference. In addition, the function of the claimed agent, therapeutic activity, is innate to the agent itself, and was not created or altered by the inventor. In sum, the claimed therapeutic and/or diagnostic agent is different, but not markedly different, from its naturally occurring counterpart, and thus is a natural phenomenon exception.
There is no evidence on record that mixing the claimed peptide with the claimed therapeutic and/or diagnostic agent changes the structure, function, or other properties of either the peptide or therapeutic and/or diagnostic agent in a marked way. Thus, for at least one embodiment of the claim with the BRI (e.g. wherein the therapeutic and/or diagnostic agent is a natural product such as paclitaxel), the claimed mixture as whole does not display markedly different characteristics compared to the naturally-occurring counterparts. Instead, the peptide and therapeutic and/or diagnostic agent have the same characteristics in the mixture as the individual components, the same chemical structure and the same function of membrane-activity and therapeutic/diagnostic activity. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). Furthermore, the claim does not even require that the two components be mixed into the same composition. Accordingly, each component, the peptide and the therapeutic and/or diagnostic agent, is a natural phenomenon exception.
Step 2A, Prong 2: The claim only recites the peptide and the therapeutic and/or diagnostic agent, which are natural phenomenon exceptions. Because there are no additional claim elements besides the judicial exceptions, the judicial exceptions are not integrated into a practical application (MPEP § 2106.04(d)(III)). In addition, because the limitation optionally formulated for intraarterial injection does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Step 2B: Because the limitation optionally formulated for intraarterial injection does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)).
Therefore, the claims are patent ineligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-4, 6-10, 13-15, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2012/083185 A1 (cited by Applicant).
WO 2012/083185 A1 discloses a composition for delivering an RNA interference polynucleotide (RNA-i) to a liver cell in vivo comprising a melittin delivery peptide and an RNA-i. The melittin delivery peptide and the RNA-i may be supplied in separate or in a single contained (page 4, lines 18-24).
The melittin peptide may have the sequence GIGAVLKVLATGLPALISWIKRKRQQ (SEQ ID NO: 80, Figure 1) and may contain an amide at the C-terminus (page 6, line 7). Therefore, the reference teaches the elected species SEQ ID NO: 1.
The RNA-i is a therapeutic agent (page 23, lines 5-15).
Therefore, WO 2012/083185 A1 satisfies all of the limitations of and anticipates instant claims 1-4, 6-10, 13-15, and 28.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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