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 .
Status of Application/Restriction/Claims
Applicant’s election without traverse of Group I (Claims 1-12) and species (targeting peptide, absence of the extra components listed in claim 3, CD206+ M macrophage, SEQ ID NO: 2 and chemotherapeutic agent) in the reply filed on 11/24/2025 is acknowledged. The species restriction between an extra component of claim 3 is withdrawn. Furthermore, applicants’ election of CD206+ M macrophage reads on the targeting peptide.
Claims 1-20 are pending. Claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-12 are examined.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/926,775 and CIP of 17/083,124 filed on 10/28/2019 and 10/28/2020, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 10/28/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/24/2024 were received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Claim Interpretation
Claim 1 broadly reads on any targeting peptide or antibody which detects a target protein within a cell. Only in claims 3 and 7 are limitations introduced further defining the targeting peptide.
Furthermore, the Lamp2b protein encoded by SEQ ID NO: 4 is interpreted as reading on the “modified” Lamp2b protein given the 112b issues discussed below.
Claim Rejections - 35 USC § 112b
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.
Claim 8 is 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 pre-AIA the applicant regards as the invention.
Claim 8 describes an engineered targeting exosome wherein “the modified Lamp2b protein” is encoded by a nucleic acid sequence with 95%, 99% or more sequence identity to SEQ ID NO: 5. There is a lack of antecedent basis for the term “the modified Lamp2b protein” since claim 1 only describes a Lamp2b signal peptide or c terminus portion of a Lamp2b protein. As a result of this indefinite term, one of ordinary skill in the art would not understand if “the modified Lamp2b protein” is referring to only the c-terminus portion of a Lamp2b protein or also the signal peptide. A claim is indefinite when it contains words or phrases whose meaning is unclear, see MPEP2173.05(e).
Claim Rejections - 35 USC § 112a, Written Description
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 1-6 and 8-12 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. This rejection is supported by Liu et al. US 2018/0104187, published 4/19/2018 (hereinafter Liu).
Claim 1 describes an engineered targeting exosome comprising a targeting peptide or antibody which detects a target protein within a cell expressing the target protein and precisely delivers the exosome to the cell.
The genus of “targeting peptide or antibody” refers to a genus that is considered extraordinarily broad. It is thought to encompass ANY fusion peptide, peptide-drug conjugate, antibody and targeting moiety. It encompasses a vast number of structurally diverse antibodies and peptides with varying affinities, stabilities and toxicities both known and yet to be discovered.
For each claim drawn to a genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, 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 procession of the claimed genius. If a representative number of adequately descried species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
The instant specification exemplifies specific CD206 binding peptides (SEQ ID NO: 2, 8, 9, 10, 11, 12 or 13). However, claim 1 broadly encompasses ANY targeting peptide or antibody that binds ANY target protein. Only in dependent claim 6 are limitations introduced specifying the target. This is not considered a representative number of samples to support the claim to all targeting peptide or antibodies given the large genus ranging from peptide-drug conjugates to any antibody both known and yet to be discovered. Given the breadth of the genus of all imagined targeting peptides or antibodies in contrast to the exemplified and prophetic proportions of the specification, which are largely drawn only to specific CD206 binding peptides, the instant specification does not adequately disclose a sufficient number of adequately described species of the genus of all postnatal cellular environments.
Furthermore, the prior art does not support the breadth of applicants claim to all targeting peptide or antibodies. In particular, the prior art reveals that each targeting peptide has a unique structure and related function which is not generalizable across all exosomes and is intentionally engineered into the design of the system. For example, Liu describes various targeting peptides on the surface of exosomes and characterizes their delivery in vitro (Liu, para 169). Liu describes a large distribution of effects and biodistributions depending on the particular targeting peptide used.
Thus, although the specification prophetically considers and discloses specific CD206 binding peptides (SEQ ID NO: 2, 8, 9, 10, 11, 12 or 13), the instant specification does not disclose a sufficient number of adequately described species to support the claim to all targeting peptides and antibodies as presently claimed.
Claim Rejections - 35 USC § 103
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 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 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.
Claims 1-5 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. US 2018/0104187, published 4/19/2018 (hereinafter Liu) in view of Qin et al. "Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice." Nature medicine 20.6 (2014): 676-681 (hereinafter Qin).
Claim 1: Liu describes engineered targeting exosomes which comprise a targeting peptide or antibody that precisely delivers the exosome to cells expressing the target protein (Liu, para 8-14, 41). Liu describes preferred embodiments towards the use of LAMP2B signal peptides and c-terminus portions (Liu, para 75 and claim 6). Liu describes the use of targeting peptides which are expressed on the surface (Liu, para 75, 81). Liu describes the use of a reporter gene for characterizing exosome expression in vitro (Liu, para 169). Liu does not describe an exosome comprising an Fc portion of IgG2b or the use of a tag protein at the C-terminus.
Claim 2: Liu describes the use of targeting peptides which are expressed on the surface of an exosome (Liu, para 75, 81).
Claim 3: Liu describes the use of targeting peptides and antibodies including CD63, CD81, LAMP2B, Tsg101 and Alix and therapeutic fusions thereof (Liu, para 75, 81 and claim 6).
Claim 4: Liu describes the use of targeting peptides involved in tumorigenesis and neurological disorders (Liu, para 51, 75, 81 and claim 6).
Claim 5: Liu describes the treatment of tumors and other neurological disorders in the brain via systemic injection of the targeted exosomes, which would penetrate through the blood brain barrier (Liu, para 51, 62 and 190).
Claim 10: Liu describes loading the targeting exosomes with cargo (Liu, para 43, 163, 237).
Claim 11: Liu describes the delivery of therapeutic or chemotherapeutic agents (Liu, claim 23).
Claim 12: Liu describes the use of a pharmaceutically accepted excipient (Liu, para 85).
Claim 1: Qin describes the use of a fusion protein comprising an Fc portion of a mouse IgG2b fused to a peptide which selectively binds a cell of interest (Qin, pg 676). Qin states that such peptides are capable of reducing tumor growth (Qin, Fig 3G and 3H). Qin further describes the use of anti-mouse IgG and anti-His tag antibodies to analyze binding specificity (Qin, Fig 2 and methods pg 682). Notably, Qin describes how using the Fc portion of a mouse IgG2b lead to enhanced antibody-dependent cell-mediated cytotoxicity (ADDC) events in targeted cells (Qin, para 680).
It would have been prima facie obvious to one of ordinary skill in the art to incorporate a fusion protein comprising an Fc portion of IgG2b as described by Qin into the targeting exosome described by Liu. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Qin provides reliable methods for generating peptibodies which incorporate Fc portion of IgG2b and could readily be adapted to the engineered targeting exosomes disclosed by Liu. One of ordinary skill would have been motivated to make this combination given that using the Fc portion of a mouse IgG2b was found to lead to enhanced antibody-dependent cell-mediated cytotoxicity (ADDC) events in targeted cells (Qin, para 680). One would have a reasonable expectation of success given that engineered exosomes carrying the IgG2b Fc region can specifically adhere to and deplete CD206-possitive M2 macrophages, which are critical for reducing tumor burden and improving survival in cancer models. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-5 and 10-12 to have been prima facie obvious to at the time the invention was made.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (supra) and Qin (supra) as applied to claims 1-5 and 10-12 above in further view of Scodeller et al. "Precision targeting of tumor macrophages with a CD206 binding peptide." Scientific reports 7.1 (2017): 14655 (hereinafter Scodeller), Wong et al. US 2017/0073382, published 3/16/2017 (hereinafter Wong) and Aburatani et al. US 2017/0152314, published 6/1/2017 (hereinafter Aburatani).
A description of Liu and Qin can be found above. Neither Liu nor Qin describe the use of a targeting peptide that targets CD206+M2 macrophages and is encoded by the elected SEQ ID NO: 2, a Lamp2b signal peptide encoded by SEQ ID NO: 4 or the Fc portion of IgG2b encoded by SEQ ID NO: 6.
Claim 6-7: Scodeller teaches the use of a targeting peptide which selectively targets tumor-associated macrophages that express CD206/MRC1 (Scodeller, pg 3). Scodeller provides methods for selecting targeting peptides and preferred embodiments towards closely related peptides reading on the elected SEQ ID NO: 2. Scodeller teaches that this peptide can deliver a payload to a tumor (Scodeller, pg 7).
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Claim 8: Wong describes methods for packing nucleic acids into exosomes for the targeted expression in neural cells (Wong, abstract). Wong discloses a Lamp2b signal peptides which share 100% sequence similarity to instant SEQ ID NO: 4 (sequence search results shown below). As stated in the claim interpretation section, the Lamp2b protein encoded by SEQ ID NO: 4 is interpreted as reading on the “modified” Lamp2b protein given the 112b issues discussed.
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Claim 9: Aburatani describes treating cancer using antibodies and provides preferred embodiments towards the use of an Fc portion of IgG2b which shares 99% sequence similarity to instant SEQ ID NO: 6 (sequence search results shown below).
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It would have been prima facie obvious to one of ordinary skill in the art to incorporate a targeting peptide that targets CD206+M2 macrophages and is encoded by the elected SEQ ID NO: 2, a Lamp2b signal peptide encoded by SEQ ID NO: 4 or the Fc portion of IgG2b encoded by SEQ ID NO: 6 into the into the targeting exosome described by Liu view of Qin. It would have been a matter of combining prior art elements according to known methods to yield predictable results since engineered exosomes carrying the IgG2b Fc region can specifically adhere to and deplete CD206-possitive M2 macrophages, which are critical for reducing tumor burden and improving survival in cancer models. One of ordinary skill would have been motivated to target CD206+ M2 macrophages using these specific targeting peptides on the exosome to achieve high specificity and reduced off-target effects. One would have a reasonable expectation of success given that the sequences of each signaling and targeting peptide are known in the art and there exists predictable methods for expressing them on engineered exosome surfaces for targeted delivery. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634