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Claims 16-27 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 5 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Drawings – Objection Withdrawn
The objection to the drawings is withdrawn in view of the amendment and arguments filed July 28, 2026.
Claim Rejections - 35 USC § 112(a) - Maintained
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), 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 peptide is required to be capable of opening a blood-brain barrier upon administration to a subject, thereby permitting deliver of at least one therapeutic and/or diagnostic agent to a central nervous system.
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 explicitly disclose the blood-brain barrier opening ability reported in the instant specification and required by the amended claims.
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.
Response to Arguments
Applicant traverses the rejection on the grounds that the specification provides multiple working examples which show that substitutions at multiple positions retain the ability to open the blood brain barrier. This argument is not persuasive because the reduction to practice is not representative of the full scope of the claims.
The genus of claimed peptides has the following structural requirement:
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291
704
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Even if the X, Z, and U residues are limited to natural amino acids, which they are not, the number of amino acid sequences that meet the requirements of the formula is limitless. Consider the definitions of each position and the number of possible combinations of amino acids.
Six X residues
Hydrophobic (W, F, Y, G, P, A, V, L, I, M, C)
116
Four Z residues
Hydrophilic or Hydrophobic
204
Two Z residues
Hydrophilic (K, R, H, T, S, D, E, N, Q)
92
Three U residues
Hydrophilic or Hydrophobic
203
Three U residues
Hydrophilic (K, R, H, T, S, D, E, N, Q)
93
These facts mean that there are 116 x 204 x 92 x 203 x 93 = 1.34 x 1020 possible sequences in the genus if the genus is limited to natural amino acids, which it is not. In contrast, the actual reduction to practice is limited to a very narrow set of sequences:
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299
678
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The species are identical at positions 1-9, 11-21, and 25. There is only a single T to A substitution tested at position 10, a single R to A substitution tested at position 22, a single K to A substitution tested at position 23, a single R to Q substitution tested at position 24, and a single Q to L substitution tested at position 26. POSITA would not consider these four closely related sequences to be representative of the 1.34 x 1020 possible sequences in the genus.
Applicant traverses the rejection on the grounds that the specification defines the structural features of the substitutions which are associated with activity, including amphipathic character and residue type. This argument is not persuasive. There is insufficient data in the specification to support the assertion of a structure-function correlation given that 21 out 26 positions have not been varied and tested, and that the five that have changed have been varied only to a limited extent.
Applicant traverses the rejection on the grounds that the working examples confirm that the blood brain barrier opening activity if not speculative. Although this point is acknowledged for the species reduced to practice, it is insufficient to overcome the rejection because the results are not representative of the full scope of the claimed peptides.
Applicant traverses the rejection on the grounds that activity does not depend on any specific interaction and the particular agent but rather depends on barrier opening. Although this point is acknowledged for the species reduced to practice, it is insufficient to overcome the rejection because the results are not representative of the full scope of the claimed peptides.
For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 112(a) – New, Necessitated by Amendment
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, 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.
MPEP § 2163 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 applicant was in possession of the claimed genus.
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 analysis above shows that there are at least 116 x 204 x 92 x 203 x 93 = 1.34 x 1020 possible sequences in the genus if the genus is limited to natural amino acids, which it is not.
Only those sequences meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, the claim encompasses all of the sequences meeting the structural requirements that are also able to open a blood-brain barrier upon administration to a subject, thereby permitting deliver of at least one therapeutic and/or diagnostic agent to a central nervous system. Although with the aid of a computer it may be possible to determine the amino acid sequences of the peptides that meet the structural requirements of the claim, it is not readily apparent from the claims or the specification which of these sequences are also able to perform the claimed function.
In contrast to the broad scope of the claims, he actual reduction to practice is limited to a very narrow set of sequences:
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299
678
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The species are identical at positions 1-9, 11-21, and 25. There is only a single T to A substitution tested at position 10, a single R to A substitution tested at position 22, a single K to A substitution tested at position 23, a single R to Q substitution tested at position 24, and a single Q to L substitution tested at position 26. POSITA would not consider these four closely related sequences to be representative of the 1.34 x 1020 possible sequences in the genus.
As discussed above the claim scope is potentially enormous depending on how many of the sequences that meet the structural requirements are also able to open the blood brain barrier and deliver a therapeutic and/or diagnostic agent of any structure and size to the brain; in comparison, the scope of the description which only includes four species of peptide and one species of agent, is extremely narrow. The actual reduction to practice does not include species characterized by variation at positions 1-9, 11-21, and 25. Therefore, one of ordinary skill in the art would not consider the reduction to practice to be representative of the full scope of the claimed genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The specification does not describe a general correlation between structure and function for the claimed genus. Although applicant asserts that the specification defines the structural features of the substitutions which are associated with activity, including amphipathic character and residue type, there is insufficient data in the specification to support this assertion. The specification does not include variation at 21 out 26 positions in the peptide. The five positions that have changed have been varied only to a limited extent. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed activity. This is especially true given the nature of the technical field. There is a high level of unpredictability and complexity associated with the opening of the blood-brain barrier and delivery of therapeutic and diagnostic agents to the brain. See specification at para. [05]-[10] as well as NPL3-NPL5 cited by Applicant on the IDS filed 4/30/2024.
Solid state peptide synthesis and the cloning, recombinant expression and purification of proteins is well-known in the art. Where the specification fails to provide description is in the structure of the peptide to make. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the structural requirements of the claims would also be able to open the blood brain barrier and deliver the therapeutic and/or diagnostic agent to the central nervous system. The specification does not make clear which peptides are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which peptides to make.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention. In conclusion, only the species actually reduced to practice, satisfy the written description requirements of 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 112(b)- withdrawn
The rejection of claims 1-4, 6-10, 13-15, and 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment and arguments filed July 28, 2026.
Claim Rejections - 35 USC § 101 - withdrawn
The rejection of claims 1-4, 6-10, 13-15, and 28 under 35 U.S.C. 101 is withdrawn in view of the amendment and arguments filed July 28, 2026.
Claim Rejections - 35 USC § 102 - maintained
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 that the composition comprises the elected species SEQ ID NO: 1.
The RNA-i is a therapeutic agent (page 23, lines 5-15).
Therefore, the reference teaches that the composition comprises the elected species SEQ ID NO: 1 and at least one therapeutic agent, meeting the structural limitations of claims 1-4, 6-10, 13-15, and 28.
Response to Arguments
In the response filed July 28, 2026, Applicant traversed the rejection on the grounds that the reference fails to teach that the peptide opens a blood-brain barrier upon administration.
MPEP § 2112.01(II) states: "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
In the instant case, the prior art teaches a composition comprising the elected species SEQ ID NO: 1 and at least one therapeutic agent, an RNA-i, but is silent as to the ability of the peptide to open a blood-brain barrier upon administration. Because the prior art teaches a composition that meets all of the structural and physical limitations of the claim, the claimed property of opening a blood-brain barrier and thereby permitting delivery of the RNA-i to the central nervous system is inherent to the prior art composition. The inventors have found a new property of an old composition and such a discovery does not constitute a new composition.
Therefore, WO 2012/083185 A1 satisfies all of the limitations of and anticipates instant claims 1-4, 6-10, 13-15, and 28.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 8:30 am - 5 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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 M MARCHETTI BRADLEY
Primary Examiner
Art Unit 1654
/CHRISTINA M MARCHETTI BRADLEY/Primary Examiner, Art Unit 1654
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