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 . 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.
Election/Restrictions
Applicant’s election without traverse of the compound ND1-YL2 to treat breast cancer in the reply filed on 1 Dec, 2025 is acknowledged. Note that the drawing of the elected structure in the response to election/restriction is difficult to make out and appears to have lost some features due to poor resolution/image transfer, so the sequence of ND1-YL2 in fig 4A is examined.
Applicants have elected ND1-YL2 to treat breast cancer. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 1, 2, 4-6, 10-12, and 15-16 were examined and claims 3, 7-9, 13, and 14 were withdrawn from consideration. While applicants state that they believe their election reads on claims 3 and 13, claim 3 requires the linker to be an ether, alkyl, alkenyl, or alkynyl, attached by amide bonds rather than the oligoalanine of the elected species, claim 13 requires multiplicity not found in the elected species, and claim 14, while supposedly describing a compound of formula 5 that reads on the elected species, has a different structure (note the proline derivatives in that sequence compared to the prolines of applicant’s elected species, for example). Thus, these claims are appropriately withdrawn.
During examination, a reference was found that anticipated a non-elected species. That reference is discussed below.
Claims Status
Claims 1-16 are pending.
Claims 3, 7-9, 13, and 14 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 1 Dec, 2025.
Specification
The disclosure is objected to because of the following informalities: in the sequence listing, both SEQ ID 1 and SEQ ID 16 are null vectors; no peptide is described. In addition, there are places where applicants have given peptide sequences, without appropriate SEQ ID numbers, note p8-11, for example. If a sequence is listed, either as a drawing or as a text sequence, the assigned sequence identifier must also be used (MPEP 2422.03).
Appropriate correction is required.
Drawings
The drawings are objected to because they contain sequences without appropriate SEQ ID numbers. The MPEP states that "It should be noted that when a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the sequence listing and the sequence identifier ("SEQ ID NO:X") must be used, either in the drawing or the brief description of the drawings” (MPEP 2422.02). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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, 2, 4-6, 10-12, 15, and 16 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would understand what structures will bind to either ubiquitin ligase or SRC-1.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants appear to have used RLAA for binding to ubiquitin ligase, and LLPPTEQDLXKL”Cha”XY (X=(S)-2(4-pentenyl)alanine) and some conservatively substituted variants for binding to SRC-1. The examples appear to almost exclusively use applicant’s elected species.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants have claimed a construct that binds to both SRC-1 and one of three E3 ubiquitin ligases. These are functional requirements that the construct have an attractive interaction with both SRC-1 and an E3 ubiquitin ligase. However, aside from specific peptide sequences, applicants have not described what structure is required to meet these functional limitations. A person of skill in the art would not know what sequence/hydrophobicity/aromaticity requirements are necessary to meet these functional limitations. In essence, applicants have claimed their invention by function. That is not sufficient to meet the written description requirement.
Reynolds et al (PLoS ONE (2011) 6(7) e22471) describes identifying the binding partner of sequences from a phage screen (abstract). In the screen used as an example, 6 phage clones bound to annexin A2, and 5 bound to vimentin (table 1, 6th page, 1st column, bottom of page). Note that there does not appear to be a consensus sequence for either target – in other words, there is no requirement that any peptide that binds to a given target resemble a second peptide that binds to the same target (although not necessarily to the same location on the target).
Seitz et al (ChemBioChem (2008) 9 p1318-1322) describe the binding between NCoA-1 (same as SRC-1) and STAT 6 (title). A structure of NCoA-1 bound to a peptide from STAT 6 is shown (fig 1, p1318, 2nd column). Note that this is very similar to the sequences applicants are using to bind to SRC-1 (compare the sequences of fig 1 (p1319, 2nd column, top of page) with SEQ ID 1 of applicants). An alanine mutation was conducted to show which residues are important for activity (table 2, p1320, bottom of page). This shows that a person of skill in the art would know which variants of YL2 of fig 4 would bind, but such a person cannot extrapolate to other sequences that would bind to SRC-1.
Shanmugasundaram et al (J. Biol. Chem. (2019) 294(4) p15172-15175) describes PROTAC design (title) states that a single residue of Arg, His, Lys, Leu, or Ile at the N-terminus of a sequence is all that is necessary to bind to UBR1 (p15172, 2nd column, 3d paragraph). Note that this list of amino acids is overlaps, but is distinct from the N-terminal amino acid of the peptide of claim 12, which binds to the same protein. Choi et al (Nat. Struct. Mol. Biol. (2010) 17(10) p1175-1182) shows that additional amino acids will affect binding (fig 2, p1178, 1st column, top of page).
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds from the screen (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, even after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: All of applicant’s examples use one of the compounds of claim 14, which all use the same ubiquitin binding agent, and variants of a single sequence for the SRC-1 binding agent. Given that there is no requirement that the binding agent on either end of the claimed PROTAC bind to the same sites on these proteins, there is no expectation that a polypeptide binding agent have any identity to these sequences. And except for the Markush claim, no claim requires that both binding moieties be peptides. This means that the universe of compounds that meet the structural limitations of the claims is infinite. With only a small number of very similar compounds, it is not possible for a person of skill in the art to extrapolate from those compounds to determine if any compound will meet the functional limitations of the claims. Thus, the claims lack written description.
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.
first rejection
Claims 1, 2, 4-6, 10-12, 15, and 16 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, and claims dependent on it, requires a binding unit to one of the ubiquitin E3 ligases, a linker, and a binding unit to SRC-1. The issue is that the cutoffs between the various parts of the construct are arbitrary. For example, Choi et al tests a sequence RLAAA for binding to UBR1. (fig 2, p1178, 1st column, top of page). Applicant uses the sequence RLAA for the same purpose (fig 4A and 4B). Shanmugasundaram et al states that the N-terminal Arg residue is sufficient (fig 1, p15173, top of page). Applicant’s elected construct is RLAAAA-SRC-1 binding sequence. If we use applicant’s sequence as the UBR1 binding sequence, the linker is AA. If we use Choi et al, it’s a single Ala residue. If we use the binding sequence of Shanmugasundaram et al, the linker is LAAAA. It is not unreasonable for someone to look at Choi et al, and conclude that the additional Ala residue should be part of the UBR1 binding sequence, to increase helicity. In that case, there would be no linker, and the construct would not read on the claims. In other words, the presence or absence of a linker in a given embodiment is arbitrary, dependent on the whim of the person designing the embodiment, but the claims require the linker.
second rejection
Claims 5, 11, and 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.
Claims 5 and 11 require SEQ ID 1 and SEQ ID 16, respectively. However, the sequence listing does not describe a SEQ ID 1 or a SEQ ID 16; those positions in the listing are blank. This makes it unclear what exactly is claimed.
third rejection
Claims 15 and 16 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 15 is a method of preventing or treating diseases caused by an overexpression of SRC-1, while claim 16 discusses a number of diseases, including immune related diseases and cancers. These are not caused by excess SRC-1 (although that protein may be involved in their etiology). For example, the NIH web page on asthma (downloaded 2025) states that the cause is unknown, but is likely different from person to person (1st page, 1st paragraph). The MedLine plus web page on breast cancer (downloaded 2025), applicant’s elected disorder, states that breast cancer is caused by changes in genetic material, the cause of which is not known (1st page, 5th paragraph). This is not SRC-1 overexpression. Because of these discrepancies, it is not clear how the phrase “caused by overexpression of SRC-1” is to be interpreted, as the plain meaning of the term is clearly incorrect.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 2, 15, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shanmugasundaram et al (J. Biol. Chem. (2019) 294(4) p15172-15175).
Shanmugasundaram et al discuss a PROTAC that binds to UBR1 (p15172, 2nd column, 3d paragraph) to treat breast cancer (p15173, 1st column, 1st paragraph). The structure is either Arg or His (identified as binding to UBR1) attached by their carboxyl group to a propyl-triazole (identified as a linker), which is connected to a small molecule which has every structural feature that applicants have stated is required to bind to SRC-1 (fig 1, p15173, top of page), so will inherently do so.
Shanmugasundaram et al describe a construct with a UBR1 binding agent, connected via a linker to a small molecule that has every structural feature applicants have stated is required to bind to SRC-1, anticipating claims 1 and 2.
Shanmugasundaram et al mentions using the construct to treat breast cancer, anticipating claims 15 and 16.
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.
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.
first rejection
Claim(s) 1, 2, 4-6, 10-12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al (Bioessays (2018) 40 article 1700247) in view of Lee et al (J. Am. Chem. Soc. (2017) 139 p16056-16059), Choi et al Nat. Struct. Mol. Biol. (2010) 17(10) p1175-1182) and Sims et al (Mol. Cell (2009) 33(6) p775-783)
Gu et al discuss PROTACs for protein degradation (title). This is a ligand that binds to an E3 ligase, attached via a linker to a ligand that binds with the protein targeted for degradation (2nd page, 1st column, 2nd paragraph). Note that various ligands to specifically target proteins to recruit them to the E3 ligase can be used, and there are a large number of E3 ligases that can be targeted (2nd page, 2nd column, 2nd paragraph). This is a better and more efficient strategy than small molecule inhibition (2nd page, 1st column, 1st paragraph) – this is more complete than inhibiting one aspect of protein function (9th page, 1st column, 2nd paragraph).
The difference between this reference and the examined claims is that this reference, while giving a general overview of PROTACs, does not describe the specific parts used by applicants.
Lee et al discuss inhibiting the NCOA-1 (another name for SRC-1) interaction with STAT6 (title). A 15 amino acid segment of STAT6 was optimized to bind to NCOA-1 (p16056, 2nd column, 3d paragraph), which can be used to treat cancers and inflammatory allergic diseases (p16056, 2nd column, 2nd paragraph). Among the sequences developed was YL-2, identical with positions 7-21 of applicant’s elected species. Note that this sequence had the best binding of all the sequences tested (fig 2, p16057, 1st column, middle of page), and did not bind to a protein with a similar binding site, suggesting specificity (p16057, 2nd column, 1st paragraph). This sequence had excellent cellular uptake compared to a cell penetrating peptide (p16057, 2nd column, 4th paragraph, continues to p16058, 1st column, 1st paragraph). This reference discusses a binding agent to a protein involved in cancer and inflammatory allergic diseases.
Choi et al discuss recognition patterns of UBR1 (abstract). Among the strongest binding segment is RLAAA (fig 2, p1178, 1st column, top of page, p1180, 1st column, 2nd paragraph). Note that this is identical to positions 1-5 of applicant’s elected compound. This reference discusses sequences that bind to UBR1.
Sims et al discuss linkages between various UIMs in Rap80 govern ubiquitination (abstract). The linker was varied by length, between 1 and 9 Ala residues, followed testing activity (5th page, 1st paragraph). There was a strong variation of binding with linker length, which is explained as matching a helix structure (5th page, 1st paragraph). This reference discusses using Ala based linkers and optimizing their length.
As Gu et al state that PROTACs are expected to be better than small molecule inhibitors, it would be obvious to generate a PROTAC targeting SRC-1, to provide a better method of treating the inflammatory immune issues and cancers of Lee et al. As Gu et al strongly suggest that this is a superior approach, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to use the binding sequence of Lee et al to target the PROTAC of Gu et al to SRC-1, as that particular sequence strongly bound and was able to cross the cell membrane. As this is a subgenus of the genus of Gu et al (targeting ligands), an artisan in this field would attempt this modification with a reasonable expectation of success.
In addition, it would be obvious to use the sequence of Choi et al to bind to UBR1 in the construct of Gu et al, as this binds to a ubiquitin E3 ligase, which is what Gu et al states is needed for the PROTAC to be active. As this is a subgenus of the genus of Gu et al (E3 ligase targeting agent), an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to use an Ala linker, and to optimize the length of the linker to maximize efficacy, as described by Sims et al, as a substitution of one known element (the unspecified linker of Gu et al) for another (the Ala linker of Sims et al) yielding expected results (connection and activity). With regards to the length of the linker, the MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II).
This renders obvious ND1-YL2, applicant’s elected species, rendering obvious claims 1, 2, 4-6, and 10-12.
Lee et al states that this can be used to treat inflammatory immune responses and cancers, rendering obvious claim 15.
second rejection
Claim(s) 1, 2, 4-6, 10-12, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al (Bioessays (2018) 40 article 1700247) in view of Lee et al (J. Am. Chem. Soc. (2017) 139 p16056-16059), Choi et al Nat. Struct. Mol. Biol. (2010) 17(10) p1175-1182) Sims et al (Mol. Cell (2009) 33(6) p775-783), and Walsh et al (Int. J. Biol. Sci. (2012) 8(4) p470-485).
The teachings of Gu et al, Lee et al, Choi et al, and Sims et al were given above, and will not be repeated here. Note that those references render obvious claism 1, 2, 4-6, 10-12, and 15.
The difference is that, while Lee et al mentions SRC-1 with respect to cancer, the reference does not mention breast cancer, applicant’s elected species.
Walsh et al discuss the function of SRC-1 in cancer (title). This protein has very low expression in human mammary gland ductal epithelial cells, but it is found in a significant number of breast tumors, and is associated with large, high grade tumors, disease recurrence, and resistance to endocrine therapy (p476, 2nd column, 2nd paragraph). It activates Ets2, which promotes breast tumor cell survival, metastasis, and resistance to some types of chemotherapy (p477, 1st column, 5th paragraph, continues to 2nd column, 1st paragraph). This reference shows that SRC-1 plays a role in breast cancer.
Therefore, it would be obvious to use the construct rendered obvious by Gu et al, Lee et al, Choi et al, and Sims et al to treat the breast cancer of Walsh et al, as Walsh et al shows that SRC-1 plays a role in that cancer. As this is a subgenus of the genus of Lee et al (cancer) that can be treated by inhibition of this protein, an artisan in this field would attempt this therapy with a reasonable expectation of success.
Conclusion
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/FRED H REYNOLDS/PRIMARY EXAMINER, ART UNIT 1658