DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01 April, 2026 has been entered.
Claims 1, 2, 8-13, 15, 17, 18, 22, 25, 26, 30, 31, and 160-176 were previously pending.
Claims 1, 11-12, 18, 26, 30-31, 160-161, and 169-170 are amended. Claims 2, 165, 167-168, 171-172, and 175-176 are cancelled.
Therefore, claims 1, 8-13, 15, 17-18, 22, 25-26, 30-31, 160-164, 166, 169-170, and 173-174 are pending and under examination in the present Official Action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/883,319 and PRO 62/947,228 filed on 06 August, 2019 and 12 December, 2019, 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 06 August, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01 April, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 21 December, 2020 were previously accepted by the Examiner.
Withdrawn Objections/Rejections in view of Applicant’s Arguments or Amendments
Claim Rejections - 35 USC § 112
The rejection of claims 1-2, 8-13, 15, 17-18, 22, 25-26, 30-31, 160-169, and 171-176 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicant’s amendments to the claims. Applicant has cancelled claims 171-172 and amended the claims to correct all outstanding issues of indefiniteness previously raised with respect to the listed claims.
The rejection of claims 175-176 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 for presenting new matter is withdrawn in view of Applicant’s amendments to the claims. Applicant has cancelled claims 175-176.
Nonstatutory Double Patenting
The rejection of claims 1-2, 8-13, 15, 17-18, 22, 25-26, 30-31 and 160-176 on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of US Patent No. 11674130 in view of Huber and Rodriguez is withdrawn in view of Applicant’s arguments.
Applicants argue that the present invention is distinct from the invention of the reference patent because Huber teaches soluble fusobodies and does not teach insertion of said fusobodies in the membrane. Remarks at 10. As conceded previously by the Examiner, solubility of the fusobodies of Huber is a stated advantage, thus, a person having ordinary skill in the art would not be motivated to remove the stated advantage by inserting the soluble fusobody of Huber into the membrane of an exosome. Arguments against the application of Huber in this context were found persuasive in the final rejection mailed 01 December, 2025, and are again found to be persuasive. Accordingly, this rejection is withdrawn.
Maintained Grounds of Objection/Rejections in Response to Applicant’s Arguments or Amendments
Claim Rejections - 35 USC § 112b
Claim 170 remains 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.
Amended claim 170 is indefinite in its recitation of “partially fragmented” . The term "partially fragmented" in claim 170 is a relative term which renders the claim indefinite. The term "partially" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Claim Rejections - 35 USC § 112a
Claims 1, 8-13, 15, 17-18, 22, 25-26, 30-31, 160-164, 166, 169-170, and 173 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 claims contain 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.
Applicant has amended claim 1 to delete all reference to a SEQ ID NO. Instead of specifying any sequence, claim 1 now generally requires only “a CD47 polypeptide”. It is unclear how this amendment narrows the scope of the instant claims as it appears to plainly expand the scope to encompass any polypeptide which can be considered “a CD47 polypeptide”. Under the broadest reasonable interpretation of “a CD47 polypeptide”, this language encompasses fragments of CD47 (Specification, [0049]) which “can refer to a locus of a protein that has less than the full length of the protein and optionally maintains the function of the protein” (Specification, [0050]). Read in light of the specification, the amended claim scope encompasses innumerable species of polypeptides which are not even required to maintain their function so long as those polypeptides “identifiably map to” CD47 (Specification, [0049]).
The instant claims are broadly directed to an extracellular vesicle comprising a polynucleotide which encodes a hybrid targeting polypeptide wherein the hybrid targeting polypeptide comprises a heterologous targeting domain and an adapter polypeptide which is a CD47 polypeptide with the function that the targeting polypeptide that is covalently linked to said extracellular domain of said adapter polypeptide (e.g., a CDX peptide (FKESWREARGTRIERG (SEQ ID NO: 104)) for U87 targeting, and a CREKA for GL261 targeting) is expressed in extracellular vesicles released from an extracellular vesicle donor cell (See Fig. 8A). Thus, the instant claims are broadly directed to a genus of extracellular domain of said adapter polypeptide that are functionally capable of expressing targeting polypeptide in extracellular vesicle donor cell and in secreted extracellular vesicles. Applicants have disclosed fusion proteins comprising a single species of CD47 that has the functional property of expression on secreted exosomes (Specification, [00188]-[00189]; [00195]-[00197]; SEQ ID NO: 1; [0081]). It is noted that the only disclosed species is full-length human CD47 and no species are disclosed having anything less than 100% identity to human CD47, let alone having any fragment of CD47. Claim 173 requires at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 while claim 174 requires the full-length amino acid sequence set forth in SEQ ID NO: 1. Note that claim 174 is omitted from this rejection.
Applicants are claiming an undefined number of polypeptides having any CD47 which, broadly construed, encompasses fragments of CD47. The narrowest embodiment of the rejected claims encompasses an adapter polypeptide which has 95% sequence identity to “the amino acid sequence set forth in SEQ ID NO: 1”. SEQ ID NO: 1 is 323 amino acids long. Therefore, even the narrowest embodiment allows for variation of any 16 amino acids within SEQ ID NO: 1. Taken together, claim 1 reads on a genus of polypeptides of variable lengths and sequences which may be considered a CD47 polypeptide, including fragments of CD47 which may or may not still possess CD47 function while claim 173 still allows for variation of 16 amino acids of SEQ ID NO: 1 which encompasses a contiguous stretch of any amino acid (including prolines which introduce bends and amino acids with large aliphatic side chains like tryptophan). The specification prophetically discloses that such an undefined genus will have the function of exosome expression (Specification, [0082]). However, the specification is silent as to what portions of the CD47 polypeptide are responsible for the functional property of exosome expression observed when full length SEQ ID NO: 1 is used. The Specification teaches that the CD47 can be purchased and cell transfection with the CDX-CD47, CREKA-CD47 plasmid (paragraph [0198]). The specification teaches that two different peptides, a CDX peptide (FKESWREARGTRIERG (SEQ ID NO: 104)) for U87 targeting, and a CREKA for GL261 targeting, and a FLAG epitope, were inserted into the N-terminal of CD47, separately, and that the N-terminal of CD47 was localized to the external exosome surface (FIG. 8B).(para [0189]). Moreover, “The addition of targeting peptide dramatically increased the CD47-exosome (Exo-T) uptake in U87 and GL261 cells, as well as translation of PTEN protein (FIG. 8C-F, FIG. 9, and FIG. 10A-D).” (paragraph [189]). This disclosure is not deemed to be descriptive of the complete structure of a representative number of polypeptide sequences encompassed by the instant claims as one of skill in the art cannot envision all the fragments of CD47 functionally able to enable expression of fusion proteins on secreted exosomes. The specification does not teach regions or domains of CD47 or the specific SEQ ID NO: 1 for that matter that are essential for the claimed activity. The specification describes five transmembrane domains within SEQ ID NO: 1 but does not describe which are essential for enabling exosome expression (Specification, [0081]). Further, the extracellular domains span the transmembrane domains and the specification fails to teach any fragment exclusively expressing the extracellular domain or exclusively expressing a transmembrane domain without their respective flanking transmembrane/extracellular domains (Specification, [0081]). Hence, there is no structure/function relationship taught at all for the amino acid sequence of SEQ ID NO: 1 and a heterologous targeting domain that is covalently linked (e.g, a CDX peptide (FKESWREARGTRIERG (SEQ ID NO: 104)) for U87 targeting, and a CREKA for GL261 targeting) that dramatically increased the CD47-exosome (Exo-T) uptake in U87 and GL261 cells. To the extent that a structure/function relationship can be gleaned from the instant specification, it is with respect to full length CD47 only and one polypeptide of 100% identity to SEQ ID NO: 1 where the N-terminal of CD47 is functionally linked to a heterologous targeting domain.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In disclosing only a single CD47 polypeptide (SEQ ID NO: 1) where the N-terminal of CD47 is functionally linked to a heterologous targeting domain, applicant has not disclosed a representative number of species for the entire genus claimed because the genus claimed covers species of polypeptides of variable lengths and sequences which may be considered a CD47 polypeptide, including fragments of CD47 which may or may not still possess CD47 function and, more narrowly, species of polypeptides having a modification of any 16 out of the 323 amino acids of SEQ ID NO: 1 which encompasses a contiguous stretch of any amino acid (including prolines which introduce bends and amino acids with large aliphatic side chains like tryptophan). A skilled artisan would understand that replacing all of these residues with proline would significantly impact the functional ability of the targeting protein to be expressed on secreted exosomes. Hence, the structure/function correlation of a polypeptide is unpredictable and a skilled artisan would recognize that the vast genus claimed encompasses species whose function would be hindered if not abolished by specific amino acid substitutions.
The skilled artisan understands that one nucleotide change in a DNA molecule or one amino acid change in the polypeptide encoded by the DNA molecule could result in loss of its biological activity as demonstrated in the generation of sickle-cell anemia wherein one specific amino acid mutation gives rise to the inherited disease (Voet et al., Biochemistry, John Wiley and Sons, 1990, p. 126-129). Further, the skilled artisan also understands that the significance of particular amino acids within a peptide cannot be predicted a priori but must be determined from case to case by painstaking experimental study (Rudinger, J., Peptide Hormones. Palgrave, London, 1976. 1-7. (Page 6, “Conclusions”)) and that it is not known whether there exists an algorithm for predicting the structure of a given protein from its amino acid sequence alone (Ngo, J. Thomas, Joe Marks, and Martin Karplus., The protein folding problem and tertiary structure prediction. Boston, MA: Birkhäuser Boston, 1994. 433-506. (page 492, second full paragraph)).
The specification prophetically discloses that an undefined genus of 90% identity to a CD47 transmembrane domain or of 90% identity to amino acid positions 19-141, 198-207, or 257-268 of SEQ ID NO: 1 will have the function of exosome expression (Specification, [0082]). However, the specification is silent as to what portions of the CD47 polypeptide linked to a heterologous targeting domain are responsible for the functional property of exosome expression observed when full length SEQ ID NO: 1 is used. Thus, a skilled artisan would understand from the teachings of Voet, Rudinger, and Ngo that the results of changing any given amino acid within SEQ ID NO: 1 where the N-terminal of CD47 is functionally linked to a heterologous targeting domain would be unpredictable in relation to dramatically increasing the CD47-exosome (Exo-T) uptake in U87 and GL261 cells and that it would require significant experimentation to determine which variants of SEQ ID NO: 1 would still possess the desired function.
Claim 173 encompasses sequences 95% identical to SEQ ID NO: 1 which is 323 amino acids long. That 5 percent variance results in a situation in which if a 16-contiguous amino acid region within SEQ ID NO: 1 were independently varied among the 20 different naturally occurring amino acids, there would be 6.55 x 1020 (2016 ) different possible molecules. In fact, since variations could occur anywhere within SEQ ID NO: 1, the actual number of different molecules encompassed by the claims is orders of magnitude higher than 2016. Computer software may provide means for identification of such species, but it is not itself an adequate written description of the structure of the claimed invention. Thus, Applicant has not disclosed a representative number of species for the entire genus of sequences claimed in claims 1, 8-13, 15, 17-18, 22, 25-26, 30-31, 160-164, 166, 169-170, and 173.
Response to Arguments
Applicant argues that the amendments to claim 1 narrow the claim scope such that the specification provides sufficient written description for the entire genus claimed. Remarks, at 11). This argument has been fully considered but has not been found persuasive for the following reasons.
The amendments to claim 1 have not narrowed the scope of the pending claims but have actually expanded the scope to encompass fragments of CD47 (Specification, [0049]) which “can refer to a locus of a protein that has less than the full length of the protein and optionally maintains the function of the protein” (Specification, [0050]). Read in light of the specification, the amended claim scope encompasses innumerable species of polypeptides which are not even required to maintain their function so long as those polypeptides “identifiably map to” CD47 (Specification, [0049]). In addition, claim 173 still reads on a genus of polypeptides having 6.55 x 1020 (2016 ) different possible molecules if a 16-contiguous amino acid region within SEQ ID NO: 1 were independently varied among the 20 different naturally occurring amino acids. Accordingly, this argument has been fully considered but has not been found persuasive.
Allowable Subject Matter
Claim 174 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Other Relevant Prior Art
Pachuk et al. US2010/0323001, published 12/23/2010 (of record) = mRNA transfection of cells using electroporation.
Kalluri et al. US 2019/0117570, published 4/25/2019 (of record) = Electroporation of exosomes.
Chang et al. "3D nanochannel electroporation for high-throughput cell transfection with high uniformity and dosage control." Nanoscale 8.1 (2016): 243-252 (of record) = electroporation apparatus.
Yang et al. "Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation." Nature biomedical engineering 4.1 (2020): 69-83 (of record) = authors work.
Zhang, Ying, et al. "Recent advances in exosome-mediated nucleic acid delivery for cancer therapy." Journal of nanobiotechnology 20.1 (2022): 279. = Current state of the art for exosome-mediated cancer therapies.
WO2019028450A1, published 7 February, 2019 = International patent application describing methods of producing extracellular vesicles containing high copies of functional nucleic acids.
WO2019099440A1, published 23 May, 2019 = International patent application describing CAR-based compositions that can include a CD47 adapter polypeptide. Lists CD47 as part of a long list of possible adapters ([0182]) without teaching extracellular vesicles or the expression of any polypeptide on an extracellular vesicle.
TICCHIONI, MICHEL, et al. "Integrin‐associated protein (CD47/IAP) contributes to T cell arrest on inflammatory vascular endothelium under flow." The FASEB Journal 15.2 (2001): 341-350. = description of CD47 expressed in CD47-deficient immune cells. No discussion of extracellular vesicles or chimeric CD47 polypeptides.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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