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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13AUG2026 has been entered.
Claim Status
Applicant’s preliminary amendments received 13AUG2026 are acknowledged.
Claims 5-9 have been canceled.
Claim 1 has been amended.
Claims 18-20 are new.
Claims 1-4 and 10-20 are pending in the instant application (i.e., Claim(s) 1 and 20 is/are independent).
Priority
The present application claims priority of US Provisional Patent Application No. 63/399010, filed 18AUG2022. Applicant’s claim for the benefit of prior-filed applications is acknowledged.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Examiner notes in this instance, that the references are not in a list, rather referenced within the specification without any IDS.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings (i.e., Fig 1 shows “peptide 31” but does not identify the sequence by “SEQ ID NO:X” or the like).
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Specific deficiency - 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 the sequence in Fig 1 contains a cysteine at the N-terminus of peptide 31 (i.e., SEQ ID NO: 5), but there is no sequence in the sequence listing, which correlates to said sequence. 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
• A statement that the substitute specification contains no new matter.
Claim Objections
Claims 3 and 15 are objected to because of the following informalities:
Claims 3 and 15 appear to recite a Markush group, and as such should include “the group consisting of” between “…selected from” and the list of alternatives.
Appropriate correction is required.
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 1-4 and 10-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling and having support for:
“A peptide-drug conjugate comprising i) a peptide, ii) a linker, and iii) a drug;
wherein the peptide comprises SEQ ID NO: 5 and further comprises a cysteine at the N-terminus;
wherein the linker is bifunctional, comprising a first functional group of maleimide for conjugation to the N-terminal cysteine of the peptide and a second functional group for conjugation to the drug; and
wherein the drug is doxorubicin.” (Claims 1 and 20) (i.e., the sequence of Cys+SEQ ID NO: 5 should be identified as a new SEQ ID NO as mentioned in the sequence deficiency supra); does not reasonably provide enablement or support for more.
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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Vrettos, et al., teaches that peptide-drug conjugates (PDCs) are consists of three building blocks: the tumor-homing peptide, the cytotoxic agent (i.e., the drug or payload), and a (biodegradable) connecting linker, each of which requires consideration upon construction of PDCs for targeted drug delivery to malignant tumors (Vrettos, et al., Bellstein J Org Chem, 2018, 14, 930-954, herein referred to as “Vrettos”) (see entire document, specifically see abstract). Vrettos further teaches that the therapeutic efficacy of a PDC is predominantly associated with the potency of the drug and the targeting efficiency of the assembled conjugate. Thus, PDCs should possess certain features to render them appealing candidates for treatment:
The peptide contained in the PDC must bind selectively and with the optimal affinity to a certain receptor, present on the cell surface of the targeted tissues and not within their cytosol or nucleus.
The selected receptor should be uniquely expressed or overexpressed on cancer cells (usually 3-fold or higher in comparison with normal cells). Additionally, it should be expressed at sufficient levels to pump inside the cell efficacious doses of the drug.
The peptide-carrier should be constructed in such way that the conjugation with a drug or/and a fluorophore is feasible. Conjugation usually occurs on lysine, cysteine and glutamic acid via orthogonal coupling or on the free N-terminus of the peptide during solid phase peptide synthesis. Though, the conjugation site should be carefully selected, since perturbations induced in the peptide structural microenvironment may result in the abolishment of its binding affinity/selectivity to the targeted receptor.
The linker should be carefully selected to succeed in the optimal performance of the PDC. An injudicious selection may cause diminished binding affinity of the peptide to the receptor or/and reduction of the therapeutic window of the drug. Additionally, it should be enzymatically stable during the blood circulation to efficiently reach the malignant tumor site and release the payload in its microenvironment, reducing the off-target toxicity.
The cytotoxic agent should contain proper functional groups that can be linked to the tumor homing peptide or if it is not present it should be rationally installed taking into consideration the final derivative of the cytotoxic agent to retain the original cytotoxic activity. (Vrettos, p 932, last paragraph of col 1 continued to col 2).
With regards to the selection of the drug, Vrettos teaches that it must comply with certain design principles such as being amenable to linker chemistry, which either encompasses a drug comprising an intrinsic functional group for direct conjugation with the linker, such as the hydroxyl groups or NH2 group at the 3’-position of doxorubicin:
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, see Fig 4 or requires derivatization to incorporate a functional group that enables bioconjugation with the linker (Vrettos, p 936, col 1, last paragraph continued to col 2) (e.g., conversion of cisplatin which is platinum(II) to a cisplatin-based platinum (IV) maleimide:
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as taught by Conibear, et al., Bioconj Chem, 2017, 28, 2429-2439, see fig 1). The importance of PDC design is further taught in Ziaei, et al., which highlights how conjugation via the NH2 group at the 3’-position of doxorubicin (i.e., intrinsic) or via a derivative of doxorubicin (i.e., aldoxorubicin) while maintaining the same maleimide bioconjugation technique to the same N-terminal cysteine modified peptide:
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, effects the overall stability and selectivity for targeted delivery of Dox to triple negative breast cancer cells, wherein conjugate 1 was more stable under various conditions, and maintained the efficacy of free doxorubicin in TNBC cells while significantly increasing the tolerated dose in non-cancerous cells compared to free doxorubicin (Ziaei, et al., Bioconj Chem, 2019, 30, 3098-3106, see entire document, specifically see Fig 1 and conclusion section). Furthermore, in this instance, the differences in cytotoxicity in non-tumorigenic MCF10A cells between Conjugate 1 and Conjugate 2 of 38.6 μM and 15.1 μM, respectively, (Ziaei, et al., see Fig 4) suggests that the linker/drug combination impacts the off-target toxicity (i.e., not all linker-drug combinations with the same peptide will result in the same maximum tolerated doses).
Vrettos goes on to teach that another crucial aspect that should be considered during the design of a PDC is the linker tethering the peptide and the drug. The linker needs to be carefully shaped so as not to perturb the binding affinity of the peptide to its receptor and the drug efficacy. Linkers utilized in PDCs exist in different categories and vary on their length, stability, release mechanism, functional groups, hydrophilicity/hydrophobicity etc. (Vrettos, p 938, col 1, last paragraph). As taught by Alas, et al., the linker in PDCs plays a key role in the circulation time of the conjugate and release of the drug for full activity at the target site (Alas, et al., J Med Chem, 2020, 64, 216-232, see entire document, specifically see abstract and Fig 1-12). Therefore, the prior art supports that a PDC consists of three components: peptide, linker, and drug and that each component must be specifically defined because each part of the structure can strongly impact the overall functionality and therapeutic efficacy of the PDC.
The specification discloses the single structure of:
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(i.e., PDoxC), wherein the PDC comprises i) a N-terminal cysteine modified SEQ ID NO: 5 (i.e., peptide 31), ii) a heterobifunctional linker comprising maleimide (i.e., an imide) for conjugation to a cysteine and NHS-ester for conjugation to the NH2 group of the drug, and iii) doxorubicin (see Fig 1); and the in vitro cytotoxic effects of PDoxC, wherein PDoxC has similar toxicity in TNBC cells to free doxorubicin and no observed toxicity up to about 25 μM in non-cancerous MCF10A cells (see Table 4 and Fig 4A-C).
Dependent claims are also rejected for the following reasons:
Claims 2-4 drawn to the drug of the PDC, do not provide limitations around the linker or alternative derivatives of the drugs that are compatible with direct conjugation to the peptide (i.e., no linker).
Claims 10-11 drawn to further comprising essentially any linker in the PDC, do not provide limitations around the drug structures which are compatible with essentially any linker, the position of conjugation of the linker to the peptide, or the bioconjugation technique used for conjugating the linker to the peptide and due to the breadth of a linker which comprises a thioester, amide, carbamate, ester, or carbonate (i.e., exclusive of an imide group or a cyclic secondary amide, such as maleimide, see 'amides' in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, accessed 21AUG2026 and 'imides' in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, accessed 21AUG2026) with essentially any chemotherapeutic or radioactive agent, the structure of the PDC is not fully defined or supported in the specification.
Claim 12 drawn to the peptide of SEQ ID NO: 5 and the drug of doxorubicin, does not provide limitations around the linker or examples of direct conjugation of the doxorubicin to the peptide, without further modification of the peptide or the drug, nor does it provide where in the peptide the doxorubicin is conjugated;
Claim 13, drawn to a pharmaceutical composition comprising the PDC of claim 1, does not remedy the deficiencies of claim 1.
Claim 14, drawn to a method of treatment comprising administering to a cancer patient in need thereof the PDC of claim 1, does not remedy the deficiencies of the product of claim 1 and furthermore, the specification lacks support for administration of any PDC comprising SEQ ID NO: 5 to a subject in need thereof.
Claims 15-17, drawn to the method of claim 14, does not remedy the deficiencies of claim 14.
Claim 18, drawn to the peptide of SEQ ID NO: 5 and the drug of doxorubicin conjugated through a succinimidyl thioether linkage to the N-terminus of the peptide, is unclear because the peptide of SEQ ID NO: 5 does not comprise a N-terminal cysteine which would allow for maleimide conjugation (i.e., a succinimidyl thioether linkage) and does not provide the position at which the linker is conjugated to the drug (see for example, Ziaei, et al., Figs 1 and 4).
Claim 19, drawn to the PDC of claim 12, wherein the doxorubicin is conjugated to the N-terminus of the peptide still does not provide limitations around the linker or examples of direct conjugation of the doxorubicin to the N-terminus of the peptide, without further modification of the peptide or the drug.
Claim 20, drawn to a PDC, wherein the peptide comprises SEQ ID NO: 5 does not provide any limitations around the remainder of the structure of the conjugate.
Therefore given the breadth of the claims, lack of predictability in the art, lack of the breadth of structures in the working examples in the specification, it would require undue experimentation for one of ordinary skill in the art to make and use the PDC as instantly claimed, and one of ordinary skill in the art would not be able to envisage all PDC structures comprising the peptide of the amino acid sequence set forth in SEQ ID NO: 5 a priori nor given the support of the specification. Therefore, claims 1-4 and 10-20, as presently claimed are rejected because 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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Claim Rejections - 35 USC § 103
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.
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 1-4, 10-13, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Fan, et al., (Biomed & Pharmacotherapy, 2015, 70, 268-273), herein referred to as “Fan” and in view of Hossein-Nejad-Ariani, et al., (Sci Rep, 2019, 9, 1-10), herein referred to as “Hossein,” Ogiso, et al., (Cell, 2002, 110, 775-787), herein referred to as “Ogiso,” and Ziaei, et al., (Bioconj Chem, 2019, 30, 3098-3106), herein referred to as “Ziaei.”
Fan teaches an EGFR-targeted peptide-drug conjugate, wherein the PDC comprises the GE11 peptide (i.e., YHWYTPQNVI), a GGGSGGGSC peptide linker, and free DOX was modified with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) at the NH2 group of the 3’-position of doxorubicin resulting in the modified doxorubicin being conjugated to the C-terminal cysteine via disulfide bond (i.e., cleavable by reduced glutathione) (i.e., GE11-DOX) (see entire document, specifically see abstract and Fig 2A). With regards to the design of the PDC, Fan teaches that doxorubicin has been used in other PDCs resulting in more efficacious and less toxic treatments than free doxorubicin, that EGFR is a readily accessible cell surface receptor and has been increasingly used as a potential target for selective drug delivery, and therefore, the GE11 peptide which binds efficiently to EGFR with lower mitogenic activity than EGF (i.e., natural ligand for EGFR activation) provides a method of delivering doxorubicin to EGFR+ cancer cells (see section 1). Furthermore, the intracellular delivery and in vitro cytotoxicity of GE11-DOX conjugate and free DOX in high (SMMC-7721) and low (MCF-7) EGFR expressing cancer cell models were evaluated (see abstract). Fan teaches that GE11-DOX accumulated at higher levels in SMMC-7721 cells than in MCF 7 cells, while the cellular uptake of free doxorubicin was almost the same in both cells and GE11-DOX conjugate showed a lower IC50 in SMMC-7721 and EGFR-overexpressing MCF-7 (0.87 mM and 3.66 mM, respectively) than in MCF-7 (32.2 mM), compared to free DOX (0.34 mM, 1.21 mM and 1.22 mM, respectively) exhibiting specific cytotoxicity against EGFR expressing cancer cell lines (see abstract and section 3.4). Furthermore, Fan teaches that the GE11-DOX PDC could be used to increase the therapeutic index (i.e., range of concentrations in which a drug achieves a desired effect with minimal toxicity) of the broad-spectrum anticancer drug doxorubicin.
However, they do not teach: the PDC, wherein the peptide comprises SEQ ID NO: 5 and exhibits no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM; or pharmaceutical compositions thereof; or conjugation of doxorubicin at the N-terminus via succinimidyl thioether linkage; or the PDC, wherein the peptide comprises SEQ ID NO: 5.
Nevertheless, Hossein teaches small peptide ligands for targeting EGFR in TNBC, wherein the peptides are second generation analogues of GE11 (see entire document, specifically see introduction and Table 1). Specifically, Hossein teaches alanine mutagenesis screening of the GE11 peptide (i.e., peptides 6-17), peptide substitutions at Q9E (i.e., negatively charged) or N10K (i.e., positively charged) of the GE11 peptide (i.e., peptides 22 and 27, respectively), and based off of the cell uptake studies combined with molecular modeling, it is expected that GE11 and analogues thereof have similar binding motif as residues 32-43 of hEGF (i.e., natural ligand for EGFR activation, comprising E in position 40 and R in position 41) to EGFR and that peptide 22 comprising the Q9E (i.e., corresponding to E in position 40 of hEGF) substitution may benefit from an additional N10R substitution (i.e., corresponding to R in position 41 of hEGF) to better mimic hEGF binding to EGFR (i.e., peptide 22 further comprising a N10R substitution is 100% query match to SEQ ID NO: 5 of the instant application, see table below) (Table 1, In vitro cell uptake of soluble (free) peptides and Peptide 22 structure sections, and Fig 4). This is further supported by Ogiso, which teaches that the N355 side chain of EGFR makes a salt bridge with the R41 (i.e., position 10 of the GE11 peptide) side chain of EGF and that previous mutagenesis and biochemical studies showed that the guanidium group of the R41 in EGF is a critical determinant for the receptor binding (Fig 3D and p 778, col 2, first full paragraph).
Sequence identification
Amino acid sequence-underline denotes similarities between GE11 and hEGF and bold denotes positions of interest for substitution
GE11
Y
H
W
Y
G
Y
T
P
Q
N
V
I
Residues 32-43 of hEGF
N
C
V
V
G
Y
I
G
E
R
C
Q
Peptide 22 (Hossein)
Y
H
W
Y
G
Y
T
P
E
N
V
I
Peptide 22 (Hossein) with N10R substitution
Y
H
W
Y
G
Y
T
P
E
R
V
I
SEQ ID NO: 5 of the instant application
Y
H
W
Y
G
Y
T
P
E
R
V
I
Additionally, Ziaei teaches an alternative TNBC-targeting PDC, comprising a N-terminal cysteine modified peptide for binding breast cancer cells, a linker, and doxorubicin (see entire document, specifically see abstract and Fig 1). Conjugate 1 comprises a SMCC linker, wherein the NHS-ester is reacted with the NH2 group of the 3’-position of doxorubicin and the maleimide is reacted with the cysteine at the N-terminus of the peptide via a succinimidyl thioether bond (see abstract and Fig 1 (conjugate 1)). Ziaei, further teaches that the succinimidyl thioether linkage shows superior in vivo efficacy compared to disulfide-bonded antibody-drug conjugates (see p 3099, col 1, lines 2-3). The stability and cytotoxicity of Conjugate 1 was compared to Conjugate 2 (see comparison of structures below or Fig 1) and it was determined that the stability of Conjugate 1 across media (+HEPES), human serum, and pH 5 media was significantly improved compared to Conjugate 2 and maintained the efficacy of free doxorubicin when dissolved in serum-free media (i.e., pharmaceutical formulation) in TNBC cells (i.e., MDAMB231 and MDAMB468) while significantly increasing the tolerated dose in non-cancerous MCF10A cells compared to free doxorubicin (see Fig 2a, 3a, and 4 and Conclusion section).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the GE11-DOX PDC disclosed by Fan by modification of the peptide sequence to Q9E and N10R and to utilize an alternate linker or doxorubicin conjugation strategy as disclosed by Hossein, Ogiso, and Ziaei because the modified peptide sequence would provide for improved binding and specificity of the EGFR-targeted peptide and changing the peptide-linker conjugation strategy from a disulfide bond to a thioether provides a more stable construct in vivo and does not require significant modification to the drug for conjugation. One would have been motivated to do so, given the teachings of Fan that a conjugate comprising an EGFR-targeted peptide, which in this instance was GE11, used in combination with doxorubicin provided a potential method for future targeted delivery (i.e., cancer cells expressing EGFR) of the broad-spectrum drug doxorubicin (i.e., non-specific). Additionally, one would have been motivated to do so, given the teachings of Hossein and Ogiso that Q9E and N10R substitutions of the GE11 peptide would produce a more optimal EGFR-targeted peptide and the teachings of Ziaei that a maleimide conjugation would provide a more stable conjugate in vivo. There would have been a reasonable expectation of success, given the knowledge that modifications to the peptide would lead to a more specific EGFR-targeted peptide and the linker conjugation would provide a more stable construct therefore anticipating an increased maximum tolerated dose in non-tumorigenic cancer cells while maintaining toxicity for EGFR-positive cancer cells as taught by Hossein, Ogiso, and Ziaei.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, (i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter (e.g., the PDC comprising SEQ ID NO: 5 exhibits no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM)), if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
RESPONSE
Applicant’s arguments, see p 5-8, 35 USC §103 rejections section, filed 13AUG2026 that the cited references of Fan in view of Hossein do not teach or suggest each and every feature of the claims; Hossein fails to provide a reasonable expectation of success, and that the claimed PDCs provide unexpected results have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
In response to Applicant’s arguments against Fan in view of Hossein not teaching or suggesting each and every feature of the claims and Hossein failing to provide a reasonable expectation of success; Examiner has taken the argument into consideration and as a result has added support from Ogiso as discussed supra.
In response to Applicant's arguments against the references individually (i.e., Hossein failing to provide a reasonable expectation of success), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, the teachings of Hossein show that modification (i.e., Q9E) to the parent GE11 peptide provided improved properties (i.e., binding properties of peptide 22), with the explicit mention that further modification to include an N10R substitution in peptide 22, would likely be more optimal. In combination, the predictability provided by Hossein and the known simplicity of making a new peptide variant provides a reasonable expectation of success that mutations which are predicted to be successful would provide a reasonable expectation of success. However, to further support the reasonable expectation of success Examiner has added support from Ogiso as discussed supra.
In response to Applicant’s arguments that the claimed PDCs comprising SEQ ID NO: 5 exhibits the unexpected results of reduced off-target toxicity (i.e., added limitation to claim 1: wherein the PDC exhibits no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM), Examiner notes that the office does not have the facilities to determine whether each PDC comprising SEQ ID NO: 5 as taught by Fan, Hossein, and Ogiso would exhibit no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM and that such a difference would have been considered unexpected by one of ordinary skill in the art. Furthermore, as supported by Ziaei, the entirety of the peptide-drug conjugate determines the off-target toxicity, rather than solely the peptide itself.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 1-4, 13-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0251143 A1 (Fojo, et al., 11AUG2022), herein referred to as “’143” and in view of Hossein-Nejad-Ariani, et al., (Sci Rep, 2019, 9, 1-10), herein referred to as “Hossein” and Ogiso, et al., (Cell, 2002, 110, 775-787), herein referred to as “Ogiso.”
‘143 teaches a conjugate comprising a tumor targeting moiety, a stable linker, and a chemotherapeutic agent for the treatment of cancer and pharmaceutical compositions thereof (see abstract and ¶0003, ¶0165). The tumor targeting peptides (TTPs) include GE11, which targets EGFR, which is linked via a stable, non-cleavable linker to a chemotherapeutic agent such as doxorubicin, which are formulated in pharmaceutical compositions for administration of the conjugates for the treatment of breast cancer (see ¶0112, Table 1, ¶0138, ¶0165-0166, ¶0037).
However, they do not teach: the PDC, wherein the peptide comprises SEQ ID NO: 5 and exhibits no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM; or pharmaceutical compositions thereof; or the PDC, wherein the peptide comprises SEQ ID NO: 5.
Nevertheless, Hossein teaches small peptide ligands for targeting EGFR in TNBC, wherein the peptides are second generation analogues of GE11 (see entire document, specifically see introduction and Table 1). Specifically, Hossein teaches alanine mutagenesis screening of the GE11 peptide (i.e., peptides 6-17), peptide substitutions at Q9E (i.e., negatively charged) or N10K (i.e., positively charged) of the GE11 peptide (i.e., peptides 22 and 27, respectively), and based off of the cell uptake studies combined with molecular modeling, it is expected that GE11 and analogues thereof have similar binding motif as residues 32-43 of hEGF (i.e., natural ligand for EGFR activation, comprising E in position 40 and R in position 41) to EGFR and that peptide 22 comprising the Q9E (i.e., corresponding to E in position 40 of hEGF) substitution may benefit from an additional N10R substitution (i.e., corresponding to R in position 41 of hEGF) to better mimic hEGF binding to EGFR (i.e., peptide 22 further comprising a N10R substitution is 100% query match to SEQ ID NO: 5 of the instant application, see table below) (Table 1, In vitro cell uptake of soluble (free) peptides and Peptide 22 structure sections, and Fig 4). This is further supported by Ogiso, which teaches that the N355 side chain of EGFR makes a salt bridge with the R41 (i.e., position 10 of the GE11 peptide) side chain of EGF and that previous mutagenesis and biochemical studies showed that the guanidium group of the R41 in EGF is a critical determinant for the receptor binding (Fig 3D and p 778, col 2, first full paragraph).
Sequence identification
Amino acid sequence-underline denotes similarities between GE11 and hEGF and bold denotes positions of interest for substitution
GE11
Y
H
W
Y
G
Y
T
P
Q
N
V
I
Residues 32-43 of hEGF
N
C
V
V
G
Y
I
G
E
R
C
Q
Peptide 22
Y
H
W
Y
G
Y
T
P
E
N
V
I
Peptide 22 with N10R substitution
Y
H
W
Y
G
Y
T
P
E
R
V
I
SEQ ID NO: 5 of the instant application
Y
H
W
Y
G
Y
T
P
E
R
V
I
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the GE11 tumor targeting peptide-linker-doxorubicin conjugate disclosed by ‘143 by modification of the peptide sequence to Q9E and N10R as disclosed by Hossein and Ogiso because the modified peptide sequence would provide for improved binding and specificity of the EGFR-targeted peptide. One would have been motivated to do so, given the teachings of Hossein and Ogiso that Q9E and N10R substitutions of the GE11 peptide would produce a more optimal EGFR-targeted peptide. There would have been a reasonable expectation of success, given the knowledge that modifications to the peptide would lead to a more specific EGFR-targeted peptide therefore anticipating an increased maximum tolerated dose in non-tumorigenic cancer cells while maintaining toxicity for EGFR-positive cancer cells as taught by Hossein and Ogiso.
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, (i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter (e.g., the PDC comprising SEQ ID NO: 5 exhibits no detectable toxicity toward MCF10A cells at concentrations up to about 25 μM)), if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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