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 SEQ ID 1 attached to a modified anti-miRNA-21 in the reply filed on 6 March, 2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Applicants have elected SEQ ID 1 attached to a modified anti-miRNA-21. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 1, 2, 4-6, 12, 22, 25, and 26 were examined, and claims 3, 7-11, 13-21, 23, 24, and 27-34 were withdrawn from consideration. Applicants have stated that they believe claim 14 reads on their election, but that claim describes modifications to the RNA backbone that were not elected. Thus, that claim is properly withdrawn.
Claims Status
Claims 1-34 are pending.
Claims 3, 7-11, 13-21, 23, 24, and 27-34 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 6 March, 2026.
Specification
The disclosure is objected to because of the following informalities: applicants have listed sequences without their SEQ ID number, note paragraphs 117, 119, 122, 124, etc. The MPEP states that "37 CFR 1.821(d) requires the use of the assigned sequence identifier in all instances where the description or claims of a patent application discuss sequences regardless of whether a given sequence is also embedded in the text of the description or claims of an application” (MPEP 2422.03).
Appropriate correction is required.
Drawings
The drawings are objected to because they show sequences without the appropriate SEQ ID number, note fig 1, for example. 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, 4-6, 12, 22, 25, and 26 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 recognize a given sequence as a PD-L1 binding sequence.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants disclose SEQ ID 1 as a PD-L1 binding sequence (paragraph 22). There is no discussion of how to modify this sequence and retain binding, or any explanation of what is structurally required to bind to PD-L1.
(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 are claiming a construct comprising a PD-L1 binding peptide. This is a functional limitation that the peptide sequence must have some affinity for PD-L1. However, applicants have not discussed what structural requirements are required to meet this functional requirement. A person of skill in the art would not know what sequence/hydrophobicity/charge requirements are necessary for this function. In essence, applicants have defined part of their invention by function. That is not sufficient to meet the written description requirement.
Li et al (CN 103936835 – note that this reference is in Chinese. A machine translation is provided, and all references to a location in the reference refer to the machine translation unless otherwise noted) discusses a peptide targeting PD-L1 (title). This sequence was discovered via a phage display screen (2nd page, last paragraph). Note that a phage display screen does not tell which residues can be modified without losing activity.
Chen et al (Trans. Oncol. (2024) 40 101851) discusses anti PD-L1 antibodies (abstract), but not other sequences, well after applicant’s priority date. Note that antibodies are selected using screening processes, which do not show where they can be safely modified.
Reynolds et al (PLoS One (2011) 6(7) e22471) looked at proteomic methods of identifying polypeptide binding partners (title). A phage display screen was run on pancreatic cancer, and the binding partners for the peptides isolated discovered (2nd page, 1st column, 2nd paragraph). Note that, for the most part, there is no obvious sequence identity between sequences that bind to the same proteins (table 1, 6th page, 1st column, bottom of page). This indicates that a sequence that binds to PD-L1 need not have any sequence identity to SEQ ID 1.
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 (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, several years 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: Applicants describe 1 sequence with the required functional activity. Given that the prior art shows screening for binding sequences (which do not yield structure/activity relationships), the fact that it is not possible to determine a priori if a given sequence will bind, and that the prior art shows that random changes are likely to abrogate activity, a person of skill in the art would not be able to recognize a sequence as binding or not binding to PD-L1. 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.
Claims 1, 2, 4-6, 12, 22, 25, and 26 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, require an oligonucleotide or a “modified” oligonucleotide. Applicants have not defined “modified,” so the dictionary definition (Merriam Webster online dictionary) of “changed” is used. However, any oligonucleotide that meets the limitations of the claims must be changed, in that it has a polypeptide attached to it. This is not consistent with the “oligonucleotide or modified oligionucleotide” language of the claims, because if everything is modified, then there is no possibility of an unmodified oligonucleotide. This makes it unclear what is covered by “oligonucleotide or a modified oligonucleotide.”
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.
Claim(s) 1, 2, 4-6, 12, 22, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (CN 112717141, published April, 2021, priority to Feb, 2021) in view of Drakaki et al (J. Clin. Oncol (2017) 35(33) suppl.). Note that Lu et al is in Chinese. A machine translation is used for this rejection, and all references to locations in the reference refer to the machine translation unless otherwise noted.
Lu et al discuss a doxorubicin conjugated to a peptide to target cancer (abstract). The peptide is highly specific for PD-L1 (8th page, 7th paragraph). A working example used the sequence NYSKPTDRQYHFK with an azido group attached to the N-terminus as the targeting sequence (10th page, 5th paragraph), which was reacted with an acetylene derivative of doxorubicin (drawing at center of 10th page). Note that this comprises applicant’s elected sequence. This is also the material that was used for further testing (8th page, 10th through 13th paragraphs) which shows that it was of interest to the authors of the paper. The material was synergistic compared to doxorubicin or the peptide alone, and was of lower toxicity and had fewer side effects than the chemotherapeutic alone (12th page, 8th paragraph). Utility is for treating a large number of different cancers, such as lung, prostate, and bladder cancers (4th page, claim 9). Material was dissolved in PBS (10th page, 6th paragraph), a pharmaceutically acceptable diluent.
The difference between this reference and the examined claims is that this reference does not discuss an oligonucleotide attached to the peptide.
Drakaki et al discuss an miRNA21 inhibitor in bladder cancer (title), which is one of the cancers that Lu et al state their conjugate can be used for. The inhibitor is an antisense oligo with a LNA phosphorothioate backbone (6th and 7th lines of abstract). In vivo treatment reduced the growth and invasiveness of a bladder cancer model (14th and 15th likes of abstract). This reference describes a modified antisense miRNA 21 agent for treatment of cancer.
Therefore, it would be obvious to substitute the miRNA21 inhibitor of Drakaki et al for the doxorubicin of Lu et al, as a substitution of one known element (the doxy of Lu et al) for another (the miRNA21 inhbitor of Drakaki et al) yielding expected results (treatment of cancer). As both Lu et al and Drakaki et al describe treatment of bladder cancer, and the miRNA inhibiter alone was effective, an artisan in this field would attempt this modification with a reasonable expectation of success.
The combination of references renders obvious a PD-L1 binding peptide conjugated to a modified miRNA, rendering obvious claim 1.
The peptide comprises SEQ ID 1, rendering obvious claim 2.
The oligonucleotide is a modified anti-miRNA 21, rendering obvious claims 4-6, 12, and 22.
Lu et al discusses formulations in PBS, rendering obvious claim 25.
Claim 26 describes an intended use. There is nothing in the construct rendered obvious by Lu et al and Drakaki et al that makes it unsuitable for such use, rendering the claim obvious (MPEP 2122).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 4-6, 12, 22, 25, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 6, and 12 of U.S. Patent No. 11,015,197 in view of Lu et al (CN 112717141). Note that Lu et al is in Chinese. A machine translation is used for this rejection, and all references to locations in the reference refer to the machine translation unless otherwise noted.
Competing claim 1 describes a miRNA 21 complementary oligonucleotide modified to allow conjugation. Competing claim 6 describes the compound of claim 1 bound to albumin. Competing claim 12 describes an intended use as treatment of cancer.
The difference between the competing claims and the examined claims is that the competing claims do not explicitly discuss a PD-L1 binding sequence.
Lu et al discuss a doxorubicin conjugated to a peptide to target cancer (abstract). The peptide is highly specific for PD-L1 (8th page, 7th paragraph). A working example used the sequence NYSKPTDRQYHFK with an azido group attached to the N-terminus as the targeting sequence (10th page, 5th paragraph), which was reacted with an acetylene derivative of doxorubicin (drawing at center of 10th page). Note that this comprises applicant’s elected sequence. This is also the material that was used for further testing (8th page, 10th through 13th paragraphs) which shows that it was of interest to the authors of the paper. The material was synergistic compared to doxorubicin or the peptide alone, and was of lower toxicity and had fewer side effects than the chemotherapeutic alone (12th page, 8th paragraph). Utility is for treating a large number of different cancers, such as lung, prostate, and bladder cancers (4th page, claim 9). Material was dissolved in PBS (10th page, 6th paragraph), a pharmaceutically acceptable diluent.
Therefore, it would be obvious to substitute the sequence of Lu et al for the albumin of the competing claims, as a substitution of one known element for another, yielding expected results (cancer therapeutic). As PD-L1 inhibition is also used for treatment of cancer, an artisan in this field would attempt this modification with a reasonable expectation of success.
Alternatively, the albumin of the competing claims has every structural feature that applicants have stated is required for binding to PD-L1, so it will necessarily do so, anticipating the examined claims (except for examined claim 2).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658