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:
Species of D: neurodegenerative drugs
Species of P: SEQ ID NO: 96
in the reply filed on June 23, 2026, is acknowledged.
The elected species of P conjugated to the elected species of D was searched and is free of the art. However, this conjugate is rejected under 35 U.S.C. 112(a). The elected species of P consisting of SEQ ID NO: 96 conjugated to a GLP-1 peptide is allowable (see Allowable Subject Matter section below). The search was extended and prior art was found on a conjugate that reads on claims 123-128, 130-131, 135, and 139-142.
Claims 129, 132-134, and 136-138 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 23, 2026.
Claim Rejections - 35 USC § 112
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 123-128, 130-131, 135, and 139-142 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 claims are drawn to conjugates of a drug to the mumps virus small hydrophobic protein (MuV SH protein) or a variant, fragment, or variant of a fragment thereof. The invention is based on the discovery that a short N-terminal fragment corresponding to residues 2-11 of MuV SH, PAIQPPLYLT (SEQ ID NO: 96), is sufficient to bind to GPR125, a receptor that is expressed in cells and structures related to the blood-cerebrospinal fluid barrier (BCSFB), blood-brain barrier (BBB), and blood-testis barrier (BTB). The MuV SH2-11 peptide is sufficient to bind to the receptor, reduce epithelial tightness, and deliver a GLP-1 peptide. Based on this observation, any MuV SH protein or a variant, fragment, or variant of a fragment thereof is claimed as a drug delivery peptide capable of transporting any drug across the BCSFB, BBB, and BTB.
Claim 123 recites a conjugate of D-P (formula (I)) wherein D is a drug, and P comprises or consists of a MuV SH protein or variant, fragment, or variant of a fragment thereof. BRI of the claim term variant includes an unlimited number of substitutions, additions, and deletions. BRI of the claim term fragment includes consecutive amino acids of any length of the parent sequence.
BRI of variable D includes any active agent, with any structure, size, charge, and function. D includes macromolecules such as proteins, antibodies, peptides, and nucleic acids, as well as small molecules.
BRI of variable P includes MuV SH from any mumps strain or genotype as well as fragments of any length and variants with any substitutions, deletions or additions. 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 bind to GPR125 sufficient to deliver the drug cargo across a barrier. 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 relevant function.
As noted on pages 2-3 of the specification, there is a high level of unpredictability and complexity associated with delivering drugs across the BBB, BCSFB, and BTB. The prior art discloses numerous peptide sequences that are fragments of MuV SH as claimed. See for example Kridel et al.1 which discloses PLYLT (Table 1), which is positions 7-11 of MuV SH. However, the PLYLT peptide of the prior art is taught to have the function of being a matrix metalloproteinase 9 substrate not the function of binding to the GPR125 or delivery a drug cargo across a BBB, BCSFB, or BTB. The prior art does not present clear rules to distinguish fragments and variants of MuV SH that can bind to the GPR125 or deliver a drug cargo across a BBB, BCSFB, or BTB from those that are not capable of this function.
One embodiment of the invention is reduced to practice: SH2-11 conjugated to GLP-1 peptides, GLP-1(7-36) and exendin-4 (1-39) (Figures 12-13). Examples 8-10 demonstrate that the SHE(2-11)-GLP-1(7-36) conjugate has a higher central anoretic effect than the unconjugated GLP-1, indicated that a high amount of the conjugate enters the brain. The same effect was observed for the SH(2-11_-Exendin-4(1-39) fusion (Example 11). The specification does not disclose any other MuV SH proteins, or variants, fragments, or variants of fragments thereof, or any other drugs. 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 deliver drugs; in comparison, the scope of the description which only includes a single MuV SH peptide species, is extremely narrow. The actual reduction to practice does not include species characterized by other fragment lengths or sequences. Nor does the actual reduction to practice include drugs of other structures, sizes, charges, or functions. Therefore, one of ordinary skill in the art would not consider SH(2-11) conjugated to GLP-1 peptides 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 data presented in the specification raise more questions about the physical properties and structure-function correlation of the genus than they answer. The data do not suggest the physical basis for the GPR125 binding, reduction in epithelial tightness, or transport activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for function is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus. Furthermore, the data in the specification do not establish whether the ability of SH(2-11) to transport a drug is limited to GLP-1 peptides or also applies to other drugs with different structures, sizes, charges, and functions.
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 D-P, wherein D comprises or consists of a GLP-1 receptor peptide agonist, a GLP-1 derived peptide, or an exendin-4 derived peptide; and P consists of PAIQPPLYLT (SEQ ID NO: 96), wherein D is conjugated to P, optionally via a linker, satisfy the written description requirements of 35 U.S.C. 112(a).
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 123-128, 130-131, 135, and 139-142 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ying et al. (Liposome-Based Systemic Glioma-Targeted Drug Delivery Enabled by All-D Peptides. ACS Appl. Mater. Interfaces 2016, 8, 29977−29985; hereafter “Ying”).
Ying teaches the all D-peptide DA7R (DRDPDPDLDWDTDA) conjugated to PEGylated liposomes containing doxorubicin. The conjugate delivers the doxorubicin across the blood-brain barrier and exerts an antiglioma effect (p 29978 col 1 para 2-3; sections 3.3, 3.5, 3.8).
DA7R is a species in the instant genus P because it comprises a variant of a fragment of MuV SH, PPL, which is positions 6-8 of MuV SH. The D-amino acid version is a variant.
Doxorubicin is a species in the instant genus D because it is an antiglioma drug.
Therefore, the D-peptide DA7R (DRDPDPDLDWDTDA) conjugated to PEGylated liposomes containing doxorubicin taught by Ying is a species in the instant genus of Formula (I), anticipating claim 123.
Regarding claim 124, the PEGylated liposomes are a linker.
Regarding claims 125-128 and 130-131, DPDPDL is a variant of a fragment of SEQ ID NOs: 1-3, 63, 74.
Regarding claim 135, DRDPDPDLDWDTDA is a variant of PAIQPPLY because BRI of the claim term variant includes an unlimited number of substitutions, additions, and deletion.
Regarding claims 139-140, doxorubicin taught by Ying exhibits antiangiogenic effects and therefore targets a component in the CNS and has anticancer activity (p 29978 col 1 para 2-3; sections 3.3, 3.5, 3.8).
Regarding claims 141-142, Ying teaches the that the all D-peptide DA7R (DRDPDPDLDWDTDA) conjugated to PEGylated liposomes containing doxorubicin delivers the doxorubicin across the blood-brain barrier and exerts an antiglioma effect (p 29978 col 1 para 2-3; sections 3.3, 3.5, 3.8).
Allowable Subject Matter
The following claims drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
123. A compound comprising a structure according to formula (I):
D-P, Formula (I)
wherein
D comprises or consists of a GLP-1 receptor peptide agonist, a GLP-1 derived peptide, or an exendin-4 derived peptide; and
P consists of PAIQPPLYLT (SEQ ID NO: 96),
wherein D is conjugated to P, optionally via a linker.
Cancel claims 124-136.
137. The compound according to claim 123, wherein D is GLP- 1 or a variant, a fragment, or a variant of a fragment thereof.
138. The compound according to claim 123, wherein D is Exendin-4 or Exendin-4(1-39) (SEQ ID NO: 130) or a variant, a fragment, or a variant of a fragment thereof.
Cancel claim 139-140.
141. A method for treatment of a metabolic disorder, said method comprising administering a therapeutically effective amount of the compound according to claim 123 to a subject in need thereof.
142. A method for delivering a drug across a membrane or barrier harbouring GPR125, the method comprising providing a compound comprising said drug as defined in claim 123.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior art of Woznick (NPL 17, IDS 01/18/2024) discloses the MuVH SH protein and its cellular target (abstract) but nowhere suggests a fragment consisting of positions 2-11. In addition, Woznick fails to suggest conjugating such a fragment to a drug. Therefore, the proposed claims are novel and unobvious over the prior art.
Conclusion
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
1 Kridel et al. Substrate Hydrolysis by Matrix Metalloproteinase-9. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276, No. 23, Issue of June 8, pp. 20572–20578, 2001
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