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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-2, 7-10, 12, 14, 16, 19-20, 30-32, and 34-36 drawn to an extracellular vesicle and a protein and/or peptide) in the reply filed on June 10, 2025, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific composition as a composition comprising microvesicles from MSCs as the EV comprising annexin as a phosphatidylserine-binding protein bound to the outer surface of the EV by means of an interaction between the annexin and phosphatidylserine (PS) as the lipid on the outer surface of the EV and where the annexin is bound to an antibody as a second protein and/or peptide or cargo binding protein and/or peptide. where the composition further comprises a release system is a cis-cleaving polypeptide-based release system comprising an intein, and where the composition comprises a chloroquine as a molecule that enhances release of the EV from endosomes bound to a phosphatidylserine-binding protein) in the reply filed on June 10, 2025, is acknowledged.
Please note that in light of the Examiner’s search, the election of Species A1, i.e., regarding the EV, and A5, i.e., regarding the enhancing molecule, are hereby withdrawn.
Status of Claims
Claims 1-34 were originally filed on April 28, 2022.
The amendment received on November 11, 2022, canceled claims 3-6, 11, 13, 15, 17-18, 21, 23, 26-29, and 33; amended claims 2, 7-8, 10, 12, 14, 16, 19-20, 22, 24-25, 30-32, and 34; and added new claims 35-36. The amendment received on February 6, 2026, amended claims 2, 9-10, 12, 14, 19, and 36.
Claims 1-2, 7-10, 12, 14, 16, 19-20, 22, 24-25, 30-32, and 34-36 are claims 1-2, 8-10, 12, 14, 16, 19-20, 32, and 34 are currently pending and under consideration as claims 22 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 7, 30-31 and 35-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 June 10, 2025.
Priority
The present application claims status as a 371 (National Stage) of PCT/GB2020/052758 filed October 30, 2020, and claims priority under 119(a)-(d) to British Application No. 1915855.9 filed on October 31, 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for British Application No. 1915855.9, which papers have been placed of record in the file. Please note that the British application is in English and therefore no further action is necessary.
Response to Arguments
Applicant’s arguments, see Response, filed 2/6/26, with respect to claim objections have been fully considered and are persuasive. The objections of claims 2, 9-10, 12, and 19 have been withdrawn.
Applicant’s arguments, see Response, filed 2/6/26, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 2 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 have been withdrawn. Please note this withdrawn rejection corresponds to the 112(b) rejection for lack of antecedent basis.
Applicant’s arguments, see Response, filed 2/6/26, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 14 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 have been withdrawn.
Applicant’s arguments, see Response, filed 2/6/26, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 2 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 have been withdrawn. Please note this withdrawn rejection corresponds to the 112(b) rejection for “according one or more of (i) to (iii)” being amended to “characterized by one or more of (i) to (iii)”.
Applicant’s arguments, see Response, filed 2/6/26, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 9 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 have been withdrawn. Please note this withdrawn rejection corresponds to the 112(b) rejection for antibody fragments.
New Objections
Claim Objections
Claims 2 and 19 are objected to because of the following informalities: the claim recites in (b) “….synaptotagmin and vinculin, and a phosphatidylserine-binding variant or fragment or anyone thereof;….” in line 14. As such, the claims recite a markush group. It is respectfully requested that the claims recite, “….synaptotagmin, vinculin, and a phosphatidylserine-binding variant or fragment or any one thereof;….” In other words, a markush group should only have one “and” prior to the last encompassed species in the Markush group. Moreover, “anyone” refers to people whereas “any one” refers to any one of the preceding species. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: the claim recites where “the second protein, peptide and/or small molecule drug is selected from one or more of an enzyme, an antibody antigen-binding variant or fragment thereof, a single chain variable fragment (scFv) and a cargo-binding protein and a cargo-binding peptide.” It is respectfully requested that claim 9 recites, “the second protein, peptide and/or small molecule drug is selected from one or more of an enzyme, an antibody, antigen-binding variant or fragment thereof, a single chain variable fragment (scFv), a cargo-binding protein, and a cargo-binding peptide” in order to be grammatically correct. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: the claim recites where “the cargo protein and/or peptide is selected from one or more of an antibody antigen-binding variant or fragment thereof, a single chain variable fragment (scFv), a nucleic acid-binding protein a nucleic acid-binding peptide, a nucleic acid analogue binding protein and a nucleic acid-binding peptide; or wherein the cargo-binding protein and/or peptide is a RNA- and/or DNA-binding protein selected from the group consisting of trans-activation Response RNA-binding Pprotein 2 (TRBP2) and polycystic Kidney Disease RNA binding domain 2 (PKdsRBD2) and a RNA- and/or DNA-binding variant or fragment of anyone thereof.” As such, claim 10 recites a markush group. It is respectfully requested that claim 10 recites, “the cargo protein and/or peptide is selected from one or more of an antibody, antigen-binding variant or fragment thereof, a single chain variable fragment (scFv), a nucleic acid-binding protein, a nucleic acid-binding peptide, a nucleic acid analogue binding protein, and a nucleic acid-binding peptide; or wherein the cargo-binding protein and/or peptide is a RNA- and/or DNA-binding protein selected from the group consisting of trans-activation Response RNA-binding Pprotein 2 (TRBP2), polycystic Kidney Disease RNA binding domain 2 (PKdsRBD2), a RNA-binding variant or fragment of any one thereof, and DNA-binding variant or fragment of any one thereof.” Appropriate correction is required.
Claim 12 is objected to because of the following informalities: the claim recites, “….or the cargo is selected from the group consisting of a small molecule drug, a protein, a peptide, an antibody antigen-binding variant or fragment thereof, a single chain variable fragment (scFv)….” It is respectfully requested that claim 12 recites, “….or the cargo is selected from the group consisting of a small molecule drug, a protein, a peptide, an antibody, antigen-binding variant or fragment thereof, a single chain variable fragment (scFv)….” in order to be grammatically correct. Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 112
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 2 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 2 is directed to where (a) the lipid is the phospholipid phosphatidylserine and/or (b) the phoshatidylserine-binding protein and/or peptide is selected from one or more of annexin,….GADPH,….and/or (c) the phosphatidylserine-binding protein and/or peptide is not GAPDH, is not an annexin,….and/or (d) the composition is substantially devoid….and/or (e) the EV comprises 500 to 5000 molecules…. As such, if (b) encompasses where the phosphatidylserine-binding protein and/or peptide can be annexin and/or GADPH, it is unclear how (b) AND (c) can be a compositional embodiment when (c) is where the phosphatidylserine-binding protein and/or peptide is NOT GAPDH and/or an annexin. In other words, claim 2 utilizes “and/or” after each of the five limitations, but (b) AND (c) encompass embodiments that cannot be combined. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds with respect to the scope of phosphatidylserine-binding protein and/or peptide of claim 2.
Please note that in light of Applicant’s election of an annexin as the phosphatidylserine-binding protein and/or peptide, the Examiner is interpreting the scope of claim 2 such that (b) is annexin and (c) encompasses where the phosphatidylserine-binding protein and/or peptide is not GAPDH in order to advance prosecution.
Claim 2 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 2 is directed to where (b) the phoshatidylserine-binding protein and/or peptide is selected from one or more of annexin,….GADPH,….prothrombin,….Raf-1,….and/or a phosphatidylserine-binding variant or fragment of anyone thereof,…” Pursuant to MPEP 2173.05(h)(I), if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In the instant case, the number of variants or fragments of each of the claimed proteins is massive to the extent that an ordinary skilled artisan would be unable to envision all of the claimed variants and fragments of each of the claimed proteins. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to variants or fragments of anyone of the recited proteins.
Claim 10 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 10 is directed to where “the cargo protein and/or peptide is selected from one or more of an antibody and/or antigen-binding variant or fragment thereof, a single chain variable fragment (scFv), a nucleic acid-binding protein and/or peptide, and a nucleic acid analogue binding protein and/or peptide; optionally wherein the cargo-binding protein and/or peptide is a RNA- and/or DNA-binding protein selected from one or more of TRBP2 and PKdsRBD2 and/or a RNA- and/or DNA-binding variant or fragment of anyone thereof.” Pursuant to MPEP 2173.05(h)(I), if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In the instant case, the number of antibody variants or fragments is massive, especially given that the antibody is any antibody, to the extent that an ordinary skilled artisan would be unable to envision all of the claimed antibody variants and fragments. Similarly, the number of nucleic acid analogue binding proteins and/or peptides is massive to the extent that an ordinary skilled artisan would be unable to envision all of the claimed nucleic acid analogue binding proteins and/or peptides, especially given that the analogues are based on any nucleic acid binding proteins and/or peptides. Moreover, the number of RNA- and/or DNA-binding variant or fragment of TRBP2 and PHdsRBD2 is massive to the extent that an ordinary skilled artisan would be unable to envision all of the claimed RNA- and/or DNA-binding variants and fragments. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to antibody variants or fragments, nucleic acid analogue binding proteins and/or peptides, and RNA- and/or DNA-binding variants and fragments.
Claim 12 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 12 is directed to where “….optionally the cargo is selected from one or more of a small molecule drug, a protein, a peptide, an antibody and/or antigen-binding variant or fragment thereof, a single chain variable fragment (scFv), a nucleic acid, a nucleic acid analogue,….” Pursuant to MPEP 2173.05(h)(I), if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In the instant case, the number of antibody variants or fragments is massive, especially given that the antibody is any antibody, to the extent that an ordinary skilled artisan would be unable to envision all of the claimed antibody variants and fragments. Similarly, the number of nucleic acid analogues is massive, especially given that the nucleic acid is any nucleic acid, to the extent that an ordinary skilled artisan would be unable to envision all of the claimed nucleic acid analogues. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to antibody variants or fragments, and nucleic acid analogues.
Claim 19 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 19 is directed to where (a) the lipid is the phospholipid phosphatidylserine and/or (b) the phoshatidylserine-binding protein, optionally wherein the phoshatidylserine-binding protein is a protein and/or peptide according to one or more of (i) to (iii): (i) the lipid is the phospholipid phosphatidylserine and/or (ii) the phosphatidylserine-binding protein and/or peptide is selected from one or more of annexin,….GADPH,….and (iii) the phosphatidylserine-binding protein and/or peptide is not GAPDH, is not an annexin,…. As such, if (b) encompasses where the phosphatidylserine-binding protein and/or peptide can be annexin and/or GADPH, it is unclear how (ii) AND (iii) can be a compositional embodiment when (iii) is where the phosphatidylserine-binding protein and/or peptide is NOT GAPDH and/or an annexin. In other words, claim 19 utilizes “and/or” and “and” after each of the three limitations, but (ii) AND (iii) encompass embodiments that cannot be combined. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds with respect to the scope of phosphatidylserine-binding protein and/or peptide of claim 19.
Please note that in light of Applicant’s election of an annexin as the phosphatidylserine-binding protein and/or peptide, the Examiner is interpreting the scope of claim 19 such that (b)(ii) is annexin and (b)(iii) encompasses where the phosphatidylserine-binding protein and/or peptide is not GAPDH in order to advance prosecution.
Claim 19 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 19 is directed to where (a) the lipid is the phospholipid phosphatidylserine and/or (b) the phoshatidylserine-binding protein, optionally wherein the phoshatidylserine-binding protein is a protein and/or peptide according to one or more of (i) to (iii): (i) the lipid is the phospholipid phosphatidylserine and/or (ii) the phosphatidylserine-binding protein and/or peptide is selected from one or more of annexin,….GADPH, ….prothrombin,….Raf-1,….and/or a phosphatidylserine-binding variant or fragment of anyone thereof,…” Pursuant to MPEP 2173.05(h)(I), if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In the instant case, the number of variants or fragments of each of the claimed proteins is massive to the extent that an ordinary skilled artisan would be unable to envision all of the claimed variants and fragments of each of the claimed proteins. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to variants or fragments of anyone of the recited proteins.
Response to Arguments
Applicant's arguments filed 2/6/26 for claims 2, 9-10, 12, and 19 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 have been fully considered but they are not persuasive for the following reasons.
With respect to the rejections of claims 2 and 19 regarding recitation of “and/or”, Applicants do not appear to dispute that the scope of claims 2 and 19 encompass an embodiment where all elements (a), (b), (c), (d), and (e) are combined. Rather, Applicants argue that an ordinary skilled artisan would know that if (b) is annexin, then (c) cannot be where the phosphatidylserine-binding protein and/or peptide is not annexin (See Applicant’s Response received on 2/6/26, pg. 10-11). Pursuant to MPEP 2111 and 2173.01(I), the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
Furthermore, pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. In the instant case, for claim 2, “and/or” is recited after each recited claim element, i.e., (a) to (e). Since “and/or” is not defined in the instant specification, the plain and ordinary meaning of the terms applies. As discussed in the rejections supra, the scope of claim 2 encompasses a number of embodiments including an embodiment where each claimed element, i.e., (a) AND, (b) AND, (c) AND, (d) AND (e). The plain and ordinary meaning of “and” refers to where each element is included. Element (b) is directed to where the phoshatidylserine (PS)-binding protein and/or peptide is one of the proteins or peptides recited in a markush group. The PS-binding protein and/or peptide of (b) can be annexin or GAPDH. As such, the broadest reasonable interpretation of claim 2(b) encompasses where the PS-binding protein is annexin or GAPDH. Element (c) is directed to where the PS-binding protein and/or peptide is NOT GAPDH, is NOT annexin, is not lactadherin and/or is not a variant or fragment of GAPDH, annexin and/or lactadherin. As such, the broadest reasonable interpretation of claim 2(c) encompasses where the PS-binding protein IS NOT annexin and/or GAPDH. Although it is acknowledged the encompassed scope of (b) and (c) would be contradictory when the PS-binding protein is annexin or GAPDH and claim 2(c) excludes annexin and/or GAPDH, this contradiction is the basis for the rejection. Since the scope of claim 2 does not address this contradiction, when considering the scope of claim 2 as a whole, each encompassed embodiment of claim 2(b) cannot conflict with each encompassed embodiment of claim 2(c). In other words, each distinct embodiment of (b) cannot be inconsistent with each distinct embodiment of (c) given that the definition of “and” in “and/or” has not been redefined. It is further noted that the rejection is NOT suggesting that there are no permissible embodiments. On the contrary, it is acknowledged that claim 2 encompasses multiple distinct embodiments that are not contradictory or inconsistent with each other. However, that is not the case for ALL encompassed embodiments. Similar discussion for claim 19 applies. Therefore, contrary to Applicant’s argument, when considering the broadest reasonable interpretation of claims 2 and 19, there are embodiments that are internally inconsistent with each other.
With respect to the rejections of claims 2, 9-10, 12 and 19 regarding recitation variants, fragments and/or analogues, as stated in the rejections supra, MPEP 2173.05(h)(I) states that “….if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s).” Contrary to Applicant’s argument, the question is not whether an ordinary skilled artisan would understand what constitutes a variant or fragment, or analogue. Rather, the question is whether an ordinary skilled artisan can determine the metes and bounds (i.e., which variants or fragments of any of the proteins and/or peptides recited in claims 2(b) and 19(b)(ii) would bind to PS; which variants or fragments recited in claims 9 and 12 would bind an antigen; and which analogues bind to nucleic acid, or which variants or fragments of TRBP2 or PKdsRBD2 bind to RNA and/or DNA recited in claim 10) given the massive number of structural variants or fragments of each recited PS-binding protein and/or peptide. Although no citation is provided, as pointed out by Applicants, a variant would encompass a protein or peptide with any number of substitutions (conservative and/or non-conservative), deletions or insertions of a recited native PS-binding protein and/or peptide; and a fragment would encompass any size fragment ranging from a peptide with a single deleted residue at the N- or C-terminus to any dipeptide of any recited native PS-binding protein and/or peptide. Two specific PS-binding fragments of GAPDH taught in the instant specification, i.e., G58 and G70 peptides, are not representative of the scope of the claimed genera. Similarly, sequence identity is not recited in the claims, and thus, is not limiting in scope since a variant or fragment is not defined as requiring a specific sequence identity to a given PS-binding protein. Therefore, the fact that the function of the variants, fragments, or analogues is recited does not per se render the structure of the encompassed variants or fragments definite.
Additionally, it is acknowledged that a claim or Markush group that encompasses many species is not per se indefinite, as along as the skilled artisan can determine what falls within the scope as asserted by Applicants (Applicant’s Response received on 2/6/26, pg. 16: citing IN re Hyatt). However, the Examiner maintains that the skilled artisan would be unable to determine what falls within the scope of the claimed species because the functional limitations are insufficient to replace the structural breadth encompassed. As such, this argument is merely the argument of counsel and is unsupported by evidence or declarations of those skilled in the art. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See M.P.E.P. § 2129 and § 2144.03 for a discussion of admissions as prior art. Counsel's arguments cannot take the place of objective evidence. In re Schulze, 145 USPQ 716 (CCPA 1965); In re Cole, 140 USPQ 230 (CCPA 1964); and especially In re Langer, 183 USPQ 288 (CCPA 1974). See M.P.E.P. § 716.01(c) for examples of attorney statements that are not evidence and that must be supported by an appropriate affidavit or declaration. Applicants have provided no evidence to demonstrate that the skilled artisan can determine a representative number of species that fall within the scope of the claimed genera. Applicants are respectfully reminded that the rejections are a question of definiteness and not a question of enablement. Whether the skilled artisan is capable of performing experiments to determine which variants, analogues or fragments would fall within the scope of the claimed genera is not dispositive as to whether the skilled artisan can determine the claims’ metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In fact, the need to perform, albeit not undue, a vast array of experiments to determine which variants, analogues and/or fragments exhibit fall within the scope of the claimed genera demonstrates the Examiner’s position that without additional experimentation, the skilled artisan cannot determine the claims’ metes and bounds.
Accordingly, the rejections of claims 2, 10, 12, and 19 are maintained as Applicants’ arguments are found unpersuasive.
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.
Claims 1-2, 16, 20, 32, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahoo US Publication No. 2012/0093885 A1 published on April 19, 2012.
For claims 1-2, 20, and 34, Sahoo et al. discloses compositions of vesicles derived from stem cells (See Sahoo, abstract; [0009]). Exosomes are vesicles formed via a specific intracellular pathway involving multivesicular bodies or endosomal-related regions of the plasma membrane (See Sahoo, [0067]). Example 1 discloses that exosomes were isolated from conditioned media in which either CD34+ cells or MNCs were cultured (See Sahoo, [0126]). Electron micrographs showed that the isolated exosomes had a similar size of about 40-90 nm or 30-100 nm in diameter and had a cup-shaped morphology (See Sahoo, [0126]). Example 2 discloses flow cytometry experiments demonstrating that the exosome membrane from both CD34+ and MNCs contained the exosome surface marker protein CD63 as depicted in Figure 3a and the lipid phosphatidylserine (PS) (See Sahoo, [0127]). The presence of PS was demonstrated by its binding to annexin V as depicted in Figure 3b (See Sahoo, [0127]). Exosomes were tagged with 4-µm Latex beads (i.e., a species of immobilized support) to increase their size for detection by the flow cytometer (See Sahoo, [0127]) thereby constituting where the exosome is bound to an immobilized support as recited in instant claim 34. As such, the exosomal structure examined during flow cytometry experiments constitutes a composition (note: the only component of the instant composition is the EV) comprising an EV (i.e., exosome) further comprising a PS-binding protein (i.e., annexin V) bound to the outer surface of the exosome membrane by means of an interaction between the PS-binding protein (i.e., annexin V) and a lipid (i.e., PS) on the outer surface of the exosome. Therefore, the specific embodiment of Sahoo’s Example 2 anticipates instant claims 1-2(a), 2(b), 2(c) (i.e., not GAPDH or lactaherin), and (d), and 20(a).
For claim 16, it is noted that the scope encompasses where the composition of claim 1 is co-administered with or further comprises a molecule that enhances release of the EV from endosomes such as chloroquine. As such, when the enhancement molecule is co-administered with the composition constitutes where the structure of the composition is unaltered. In other words, an enhancement molecule such as chloroquine is not required to be a structural component of the composition. Rather, it can be part of the intended use of the composition, i.e., being co-administered.
Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed composition is intended to be co-administered with an enhancement molecule such as chloroquine thereby constituting the intended use of the composition, and thus, there is no structure imparted by such a use. Since Sahoo et al. discloses the composition structure as recited in instant claim 1 as discussed supra, the structural limitation imparted by the “wherein” clause is met. Therefore, the disclosure of Sahoo satisfies the claim limitation as recited in instant claim 16.
For claim 32, it is noted that that the scope encompasses an intended use of the composition of claim 1. Pursuant to MPEP 2112.02, the discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02. Thus, claim 32 is interpreted as reciting one or more intended uses of the composition, i.e., (a) for purifying an EV; or (b) as a research tool, a diagnostic tool, an imaging tool, biological reference material, an experimental control and/or an experimental standard. A recitation of an intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Therefore, reciting that the composition is to be used for one of the intended uses, only excludes a prior art reference if that reference expressly teaches or suggests that the composition could not be used for one of the claimed purposes. Therefore, the teachings of Sahoo et al. satisfy the claim limitation with respect to where the composition is for (a) for purifying an EV; or (b) as a research tool, a diagnostic tool, an imaging tool, biological reference material, an experimental control and/or an experimental standard as recited in claim 32.
Accordingly, the disclosure of Sahoo et al. anticipates instant claims 1-2, 16, 20, 32, and 34.
Response to Arguments
Applicant's arguments filed 5/1/26 for claims 1-2, 16, 20, 32, and 34 as being anticipated by Sahoo have been fully considered but they are not persuasive for the following reasons.
As an initial matter, the Examiner would like to point out the required structural limitations of claim 1. More specifically, the scope of claim 1 is directed to a composition comprising a single structural component, i.e., an extracellular vesicle (EV). This single structural component is modified with a heterologous moiety such that the heterologous moiety interacts covalently or non-covalently with an EV lipid or EV protein on the outer surface of the EV. As will be further articulated below, as long as a prior art reference discloses the single structural component, the prior art reference necessarily discloses a composition comprising the single structural component.
In response to Applicant’s first argument, i.e., Sahoo does not disclose a “composition” (See Applicant’s Response received on 2/6/26, pg. 17-18), it is found unpersuasive. Pursuant to MPEP 2111 and 2173.01(I), the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
Furthermore, pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. In the instant case, it is noted that the instant specification does not define what constitutes a “composition”. As such, the plain and ordinary meaning of the term applies. Although there are several definitions of what constitutes a “composition”, pertinent definitions include “the makeup of a thing or person; aggregate of ingredients or qualities and manner of their combination; constitution;” and/or “a mixture of several parts or ingredients (See Collins Dictionary, available online at https://www.collinsdictionary.com/us/dictionary/english/composition, 15 pages (accessed on June 24, 2026) at pg. 3). However, as stated supra, the claimed composition only requires a single structural component that is modified with a heterologous moiety, i.e., the extracellular vesicle (EV) having a PS-binding protein/peptide (i.e., heterologous moiety) bound to the EV outer surface via interaction with a lipid or EV protein on the EV outer surface. As such, there is no required mixture or aggregate of ingredients in the claimed composition, e.g., inclusion of a carrier or excipient. The makeup or constitution of the claimed composition is the single aforementioned structural component.
Furthermore, MPEP 2112 states that “the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103.” "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). MPEP 2112(II) states “there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.” Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (See also: Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); and Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics.") However, MPEP 2112(IV) acknowledges that the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990). In the instant case, it is acknowledged that Sahoo does not expressly refer to the modified EV as a composition. However, lack of expressed disclosure does not per se preclude anticipation. As long as a prior art reference discloses the claimed required structural component, the prior art reference necessarily anticipates the claimed composition. As acknowledged by Applicant, Sahoo expressly teaches an EV (i.e., exosome) bound to annexin V during an analytical procedure. Since the definition of a “composition” and the scope of the claimed invention do not require that the heterologous moiety remain bound to the EV outer surface for a specific time period, do not require isolation of the modified EV, do not require storage of the modified EV, or do not require use the modified EV, the modified EV generated during an analytical procedure disclosed by Sahoo necessarily exhibits the characteristic of being a composition comprising the modified EV.
Moreover, it is noted that the features upon which applicant relies (i.e., the PS-binding protein “remains stably” bound to the EV surface; claimed composition is produced or isolated; claimed composition is used for any purpose beyond the momentary detection event) (See Applicant’s Response received on 5/1/26, pg. 18) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, as discussed supra, the only structural requirement of claim 1 is the modified EV. In fact, “bound” and “via interaction” in claim 1 are not limited to covalent binding. Rather, the scope of claim 1 encompasses where the PS-binding protein/peptide is non-covalently or covalently bound to the EV lipid or protein. Plus, MPEP 2152.02(b) states that there is no requirement that a prior art document meet the "how to use" requirement of 35 U.S.C. 112(a) in order to qualify as prior art. See Gleave, 560 F.3d at 1334, 90 USPQ2d at 1237-38; see also In re Schoenwald, 964 F.2d 1122, 1124, 22 USPQ2d 1671, 1673 (Fed. Cir. 1992) (holding that a claimed compound was anticipated even though the prior art reference did not disclose a use for the compound); Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1380-81, 67 USPQ2d 1664, 1670 (Fed. Cir. 2003) (pointing out that actually reducing the invention to practice is not necessary in order for a prior art reference to anticipate); Impax Labs, 468 F.3d at 1382 (stating that "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation"). Compliance with the "how to make" requirement is judged from the viewpoint of a person of ordinary skill in the art, and thus does not require that the prior art document explicitly disclose information within the knowledge of such a person. See In re Donohue, 766 F.2d 531, 533, 226 USPQ 619, 621 (Fed. Cir. 1985). Here, since Sahoo discloses using the claimed modified EV in an analytical procedure and binding annexin V to a lipid or EV protein on the outer surface of an EV is well-known in the art (See Smyth et al., Bioconjugate Chem. 25:1777-1784 (2014) at abstract: teaching a method of conjugating ligands to the surface of exosomes via click chemistry), an ordinary skilled artisan would be well-versed in “how to make” the claimed modified EV. Therefore, contrary to Applicant’s argument, Sahoo discloses each and every element of the claimed invention expressly and inherently.
In response to Applicant’s second argument, i.e., Sahoo’s annexin V serves a different purpose (See Applicant’s Response received on 2/6/26, pg. 18), it is found unpersuasive. As stated supra, MPEP 2152.02(b) states that there is no requirement that a prior art document meet the "how to use" requirement of 35 U.S.C. 112(a) in order to qualify as prior art. See Gleave, 560 F.3d at 1334, 90 USPQ2d at 1237-38; see also In re Schoenwald, 964 F.2d 1122, 1124, 22 USPQ2d 1671, 1673 (Fed. Cir. 1992) (holding that a claimed compound was anticipated even though the prior art reference did not disclose a use for the compound); Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1380-81, 67 USPQ2d 1664, 1670 (Fed. Cir. 2003) (pointing out that actually reducing the invention to practice is not necessary in order for a prior art reference to anticipate); Impax Labs, 468 F.3d at 1382 (stating that "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation"). In the instant case, it is unnecessary for Sahoo to disclose that the modified EVs are intended to be used for functional purposes such as cargo loading, therapeutic delivery, and EV purification as asserted by Applicants. This is because there is no requirement that a prior art document meet the "how to use" requirement of 35 U.S.C. 112(a) in order to qualify as prior art, let alone the same intended use of the claimed composition. Therefore, contrary to Applicant’s argument, the fact that the annexin V disclosed by Sahoo is not used for the same purpose as in the claimed composition does not preclude anticipation of the claimed composition by Sahoo.
In response to Applicant’s third argument, i.e., claim 2 includes limitations not disclosed by Sahoo (See Applicant’s Response received on 2/6/26, pg. 18-19), it is found unpersuasive. As discussed supra, the scope of a claim is given the broadest reasonable interpretation. Claim 2 recites 5 structural components, i.e., (a) to (e). However, the scope of claim 2 does not require ALL the 5 structural components. Rather, after each component, the phrase “and/or” is utilized. “And/or” correlates to one or more of the 5 structural components. In other words, in order to satisfy the claim limitation(s) of claim 2, only 1 of the 5 structural components must be met. It is clear from the rejection supra that Sahoo discloses that the PS-binding protein is annexin V, and would inherently disclose that the PS-binding protein is not GAPDH. It is further clear that the Sahoo’s EVs fall within the claimed diameter range recited in claim 2(d). Therefore, it is unnecessary for Sahoo to disclose whether the composition is devoid of vesicle aggregates and the number of PS-binding proteins bound to the outer surface of the EV given that these structural components are recited in the alternative, i.e., “and/or”. Thus, contrary to Applicant’s argument, the fact that Sahoo does not disclose every structural component recited in claim 2 does not preclude anticipation.
In response to Applicant’s fourth argument, i.e., claim 16 is not anticipated because Sahoo does not disclose any molecule that enhances release of EVs from endosomes (See Applicant’s Response received on 2/6/26, pg. 19), it is found unpersuasive. As discussed supra, the scope of a claim is given the broadest reasonable interpretation. Claim 16 recites, “…wherein the composition is co-administered with, and/or further comprises, a molecule that enhances release of the EV from endosomes; optionally, wherein the molecule that enhances release of the EV from endosomes is:…” As such, the broadest reasonable interpretation of claim 16 is where the composition is co-administered with a molecule that enhances release of the EV from endosomes. Claim 16 does not require that the composition further comprise the molecule. As such, the molecule is not a required structural limitation of the claimed composition. Therefore, contrary to Applicant’s argument, it is unnecessary for Sahoo to disclose a molecule that enhances release of EVs from endosomes in order to anticipate claim 16 because the broadest reasonable interpretation of claim 16 encompasses where the molecule is a limitation of the claimed intended use of the claimed composition.
In response to Applicant’s fifth argument, i.e., claims 32 and 34 are not anticipated (See Applicant’s Response received on 2/6/26, pg. 19-20), it is found unpersuasive. With respect to claim 32, Applicant’s attention is direct to the response for claim 1 supra maintaining that Sahoo discloses the composition of claim 1. Furthermore, although unnecessary for Sahoo to expressly disclose one of the claimed intended uses recited in claim 32, as pointed out by Applicants, the modified EV is used in an analytical procedure thereby constituting its use as research tool or a diagnostic tool, at a minimum. Given that claim 32 utilizes the word, “or” and “and/or”, only one of the recited intended uses would need to be expressly disclosed. Thus, contrary to Applicant’s argument, the fact that Sahoo does not expressly disclose using the annexin V-bound exosomes for purifying EVs does not preclude Sahoo anticipating the claimed composition.
With respect to claim 34, as discussed supra, the scope of a claim is given the broadest reasonable interpretation. Claim 34 is directed to where the composition is immobilized to a solid support. Applicants are respectfully reminded the claimed invention is directed to a composition and not a method of use. As such, the question is whether a prior art reference discloses the claimed structure, not an unrecited use of the claimed structure. Therefore, the intended use or purpose of Sahoo attaching the exosomes to latex beads is not dispositive as to whether Sahoo discloses the claimed structure, i.e., the modified EVs attached to a solid support. However, even if intended use is given patentable weight for a composition claim, Applicants are respectfully reminded that claim 32 is not limited to EV purification, but include the modified EVs being used as a research and/or diagnostic tool. As pointed out by Applicants, Sahoo’s latex beads are attached to exosomes for detection thereby constituting use as a research and/or diagnostic tool. Thus, contrary to Applicant’s argument, Sahoo’s disclosure anticipates the structural limitation recited in instant claim 34.
Accordingly, the rejection of claims 1-2, 16, 20, 32 and 34 is maintained as Applicants’ arguments are found unpersuasive.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Sahoo US Publication No. 2012/0093885 A1 published on April 19, 2012, as applied to claim 1 above, and further in view of Ortega et al., Nanomed.: Nanotechnol., Biol., and Med. 20:1-12 (August 2019), as applied to claim 16 herewith.
For claim 1, please see discussion of Sahoo supra.
For claim 16, with respect to where the composition further comprises chloroquine as a molecule that enhances release of the EV from endosomes as recited in instant claim 16:
As discussed supra, Sahoo et al. teaches compositions of vesicles derived from stem cells (See Sahoo, abstract; [0009]). Exosomes are vesicles formed via a specific intracellular pathway involving multivesicular bodies or endosomal-related regions of the plasma membrane (See Sahoo, [0067]). Sahoo et al. teaches that the compositions can comprise purified and isolated vesicles or an extract prepared from animal adult stem cells for a medicament (See Sahoo, [0014]). An exemplary method of producing exosomes comprises culturing adult stem cells in conditioned media, isolating the cells from the conditioned media, purifying the vesicles by sequential centrifugation, and clarifying the vesicles on a density gradient (See Sahoo, [0070]). More specifically, example 1 describes that exosomes were isolated from conditioned media in which either CD34+ cells or MNCs were cultured (See Sahoo, [0126]). Thus, Sahoo et al. teaches methods of producing EVs where the EVs are derived from adult stem cells.
However, Sahoo et al. does not expressly teach where the composition further comprises chloroquine as a molecule that enhances release of the EV from endosomes and is linked to the EV via an EV membrane-bound moiety or PS-binding protein.
Ortega et al. teaches that exosomes are increasingly being studies as novel drug delivery vehicles or as cell-free approaches to regenerative medicine because of their bioactive cargo consisting of proteins, RNA and lipids and their natural ability to deliver these biomolecules to recipient cells (See Ortega, abstract; pg. 1, col. 2, 1st paragraph; pg. 2, col. 1, 2nd paragraph). However, one of the major hurdles for clinical translation of therapeutic strategies based on exosomes is their low yield when produced under standard culture conditions (See Ortega, abstract; pg. 2, col. 1, 2nd paragraph). Oretaga et al. found that when interfering with endolysosomal trafficking significantly increases exosome release and the exosomes retain their regenerative bioactivity (See Ortega, abstract). Such results can then be employed to increase exosome production for studying biological functions or to improve clinical translation of exosome-based therapeutics (See Ortega, abstract). More specifically, Oretaga et al. teaches that exosome biogenesis begins with endocytosis and ends with the degradation of the endosomal content by fusion of late endosomes with lysosomes (See Ortega, pg. 2, col. 1, 3rd paragraph). Lysosomes control whether late endosomes or multivesicular bodies are degraded or released to the extracellular environment as exosomes (See Ortega, pg. 2, col. 1, 3rd paragraph). To determine whether increased exosomal release can be achieved through inhibition of endolysosomal trafficking, Oretaga et al. used chloroquine and NH4Cl, both known lysosomotropic agents that efficiently inhibit endosomal maturation (See Ortega, pg. 6, col. 2, last paragraph). Both agents accumulate inside the acidic compartments of treated cells including endosomes and lysosomes, leading to inhibition of lysosomal enzymes which require an acidic pH and preventing fusion of endosomes and lysosomes (See Ortega, pg. 6, col. 2, last paragraph to pg. 7, col. 1, 1st paragraph). Oretaga et al. demonstrates that there was an increased release of four exosomal markers in supernatants from three tested cell lines after treatment with chloroquine (See Ortega, pg. 7, col. 1, 2nd paragraph). Plus, Oretaga et al. teaches that chloroquine treated cells resulted in an increase in exosome release (See Ortega, pg. 7, col. 2, 1st paragraph). Oretaga et al. then concludes that interfering with endolysosomal trafficking by using an agent such as chloroquine would stimulate exosome release, and thus, exosome production (See Ortega, pg. 9, col. 2, last paragraph). Thus, using an agent such as chloroquine can be employed as a strategy to facilitate clinical translation of exosome therapeutics by increasing their production thereby overcoming the low yield exosome levels achieved under standard culturing conditions (See Ortega, pg. 10, col. 2, 2nd paragraph).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Sahoo and produce exosomes derived from adult stem cells by adding chloroquine thereby constituting a composition comprising exosomes having PS on its outer membrane surface and annexin bound to the PS, and free chloroquine in order to increase exosome production in cell culture by interfering with endolysosomal trafficking. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because adding chloroquine to cell culture was known to interfere with endolysosomal trafficking thereby stimulating exosome release and production as taught by Oretaga et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the exosomes of Sahoo were produced by culturing cells in conditioned media, and therefore, adding chloroquine to the cell culture thereby constituting a composition comprising the exosomes having PS on its outer membrane surface and annexin bound to the PS and free chloroquine would support the stimulation of exosomal release and production by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 2/6/26 for claims 1 and 16 as being unpatentable pursuant to 35 USC 103(a) have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s first argument, i.e., the proposed combination does not arrive at the composition of the claims because the combination, at best, suggests exosomes in the presence of chloroquine with annexin V transiently bound during flow cytometry detection, which is distinguishable from the claimed composition (See Applicant’s Response received on 2/6/26, pg. 20-21). As discussed in the “Response to Arguments” section supra for the 102(a)(1) rejection, Sahoo expressly discloses a specific embodiment of a modified EV where annexin V is attached to PS on the outer surface of the exosome. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). As discussed in the rejection supra, Sahoo et al. teaches where exosomes can be derived naturally via isolation from a living organism or from cells grown in culture, or be synthetically assembled (See Sahoo, [0080]-[0081]). Synthetic exosomes can be assembled from the therapeutic payload to be delivered, and the particular components required by exosomes for effective delivery of their contents to recipient cells (See Sahoo, [0081]). Sahoo et al. teaches that synthetic exosomes can also utilize several proteins such as HSP70, HSP90 and annexins (See Sahoo, [0081]). As such, when considering the teachings of Sahoo et al. as a whole, the Sahoo is not limited to only the flow cytometry assay described in Example 2. Rather, Sahoo demonstrates that annexin V binds to PS on the outer surface of an exosome, and also teaches that synthetic exosomes can utilize annexins. Thus, the teachings of Sahoo are not strictly limited to the “transient” (which the Examiner does not concede) binding of annexin V to the outer surface of the exosome.
Furthermore, both Sahoo and Ortega describe cell culture methods where Sahoo describes obtaining exosomes derived from adult stem cells and/or via synthetic methods, and Ortega teaches a benefit to add chloroquine to cell culture to stimulate exosome release and production. The broadest reasonable interpretation of the elected composition of claim 16 is not limited to Applicant’s narrow composition interpretation. Pursuant to MPEP 2113.03(I), the transitional term "comprising" is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. Since the composition of claim 1 utilizes the transitional phrase “comprising”, the composition encompasses any additional components not expressly recited. As such, a cell culture media constitutes a composition of instant claim 1 that contains exosomes that can be modified with annexin V on the exosome’s outer surface via binding to the surface PS and where the addition of chloroquine interferes with endolysosomal trafficking, which in turn, stimulates exosome release and production. Therefore, contrary to Applicant’s argument, the combination of Sahoo and Ortega suggest a composition comprising modified exosomes and chloroquine.
In response to Applicant’s second and third arguments, i.e., Ortega’s chloroquine serves a fundamentally different purpose, and the claim limitation “molecule that enhances release of the EV from endosomes” is not taught (See Applicant’s Response received on 2/6/26, pg. 21-22), they are found unpersuasive. A difference in objectives, if any, does not defeat the case for obviousness because, as MPEP § 2144 states, the “reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) …; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) … .” In the instant case, it is acknowledged that Sahoo and Ortega do not expressly indicate that chloroquine functions as a molecule that enhances release of the EV from endosomes. However, Applicants are respectfully reminded that the instant claimed invention is directed to a product and not a method of using the product. As such, the fact that the combination of Sahoo and Ortega do not expressly indicate that chloroquine functions as a molecule that enhances release of the EV from endosomes does not preclude a finding of obviousness. This is further because pursuant to MPEP 2112.01(II), “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. Thus, since the combination of Sahoo and Ortega renders the claimed compositional structure obvious the combination would also necessarily render the claimed function obvious as well. Pursuant to MPEP 2112.01(I), where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Thus, given that the combination of Sahoo and Ortega renders the claimed structure of the composition obvious, the burden is on Applicant to show that the product of the Applicant and the prior art are not the same. Applicants have failed to do so. Rather, Applicants assert that because the references fail to expressly teach or suggest that the compound exhibits a functional property of chloroquine, that the obviousness rejection falls. Such an argument is unpersuasive as it does not assert why or how the prior art product (i.e., when the Sahoo and Ortega references are combined) is not the same structure as the claimed composition.
Plus, pursuant to MPEP 2112(I), the claiming of a new use, new function or unknown property which is necessarily present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Moreover, pursuant to MPEP 2112(II), where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. "There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims. Thus, it is unnecessary for the combination of references to expressly teach or suggest that chloroquine functions as a molecule that enhances release of the EV from endosomes. As discussed in the rejection supra, because the combination of Sahoo and Ortega render the instantly claimed compositional structure obvious, the combination of Sahoo and Ortega would also necessarily exhibit the claimed function of chloroquine.
In response to Applicant’s fourth argument, i.e., there is no motivation to combine for the claimed purpose (See Applicant’s Response received on 2/6/26, pg. 22), it is found unpersuasive. A difference in objectives, if any, does not defeat the case for obviousness because, as MPEP § 2144 states, the “reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) …; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) … .” In the instant case, as stated supra, Applicants are respectfully reminded that the instant claimed invention is directed to a product and not a method of using the product. As such, the fact that none of the first three stated intended uses are suggested by the combination of Sahoo and Ortega does not preclude that an ordinary skilled artisan would be motivated to combine the teachings of Sahoo and Ortega in order to arrive at the compositional structure of claim 16 where the composition further comprises chloroquine. Moreover, there is no intended use limitation even recited for therapeutic delivery or as an isolated EV composition. Therefore, contrary to Applicant’s argument, the motivational rationale utilized in the rejection, i.e., to increase exosome production in cell culture, may not be the intended purpose of the instant composition, but an ordinary skilled artisan need only to be motivated to render the structure of the claimed composition obvious as opposed to the an intended use of the claimed composition.
In response to Applicant’s fifth argument, i.e., Ortega teaches away from the claimed invention (See Applicant’s Response received on 2/6/26, pg. 23), it is found unpersuasive. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In the instant case, Ortega suggests increasing production of exosomes in cell culture by adding chloroquine to the culture media. As stated supra, Ortega’s chloroquine is structurally identical to the instant chloroquine. As such, the functional property of chloroquine as claimed must necessarily be present even if not expressly taught. Therefore, the teachings of Ortega cannot teach away because the structure of the chloroquine is identical. Thus, contrary to Applicant’s argument, Ortega does not teach away from combining the exosomal cell culture methods of Sahoo with adding chloroquine to the cell culture media as suggested by Ortega.
In response to Applicant’s sixth argument, i.e., the claimed invention addresses a long-felt need for efficient EV loading and delivery methods (See Applicant’s Response received on 2/6/26, pg. 23), it is found unpersuasive. Regarding Applicant’s assertion of a long-felt need for Applicant’s invention, it is noted that MPEP 716.04 states:
Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art…. Second, the long-felt need must not have been satisfied by another before the invention by applicant.
As such, there are two factors needed to be evaluated as to whether a long-felt need has been established. Although the specification states that there is no effective method available to load EVs with a specific molecule of interest and current methods lack efficiency and reproducibility, the Applicant has not provided objective evidence that an art recognized problem has existed in the art for a long period of time without solution. Thus, the need has not been recognized by those of ordinary skill in the art. Therefore, the first factor in establishing a long-felt need has not been met. Additionally, it is not readily apparent that the second factor has been met. Smyth et al. describes a method for conjugation of ligands to the surface of exosomes using click chemistry (See Smyth et al., Bioconjugate Chem. 25:1777-1784 (2014) at abstract). Smyth et al. concludes that click chemistry is rapidly becoming a popular tool to functionalize the surface of biomacromolecules including liposomes and micelles with a wide variety of conjugates (See Smyth, pg. 1779, col. 2, last paragraph). In Smyth’s study, the novel technique can be used to functionalize the surface of exosomes with small molecules, large biomacromolecules, and polymers (See Smyth, pg. 1779, col. 2, last paragraph). Therefore, the second factor in establishing a long-felt need has not been met.
Accordingly, the rejection of claims 1 and 16 is maintained as Applicants’ arguments are found unpersuasive.
Claims 1-2, 8-10, 12, 16, 20, 32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Brisson US Publication No. 2009/0226887 A1 published on September 10, 2009 (cited in the IDS received on 11/11/22) in view of Ha et al., Acta Pharma. Sinica B 6:289-296 (2016), alone or as evidenced by, “Dioleoylphosphatidylserine” PubChem, available online at https://pubchem.ncbi.nlm.nih.gov/compound/Dioleoyl-phosphatidylserine, 32 pages (2006) (hereinafter the “PubChem reference”).
For claims 1-2 and 20, with respect to a composition comprising an EV comprising a PS-binding protein bound to the outer surface of the EV by means of an interaction between the PS-binding protein and a lipid on the outer surface of the EV as recited in instant claim 1; with respect to where the lipid is a phospholipid PS and/or where the PS-binding protein is annexin and/or where the PS-binding protein is not GAPDH or lactadherin as recited in instant claim 2(b) and (c); and with respect to where the EV is an exosome as recited in instant claim 20:
Brisson teaches a device for binding a target entity onto a bait entity that is immobilized on the device comprising (a) a lipid layer which comprises one or more lipids, the lipid layer having a negative net charge in an aqueous solution at a neutral pH; (b) a 2D matrix of anchoring complexes that are bound to the lipid layer where each of the anchoring complexes comprise: (i) a fusion complex comprising an annexin protein fused to a partner molecule where the annexin protein is bound to the lipid layer and the partner molecule consists of an organic or a mineral compound such as a polypeptide or protein; (ii) a bait molecule selected from the partner molecule that is fused to the annexin protein; a molecule that is covalently or non-covalently bound to the partner molecule; a molecule that is indirectly bound to the partner molecule through one or more intermediate molecules that are covalently or non-covalently bound to the partner molecule (See Brisson, [0015]-[0024]; [0118]-[0127], [0149]; [0318], [0321]-[0331]). The lipid layer is selected from: (ai) a lipid bi-layer including a lipid bi-layer coating a solid substrate, (aii) a lipid mono-layer including a lipid monolayer formed at the interface between air and an aqueous solution, and (aiii) a liposome in an aqueous solution including a liposome consisting of a vesicle with one or more lipid bi-layers enclosing an aqueous core (See Brisson, [0025]-[0028]). When the lipid layer is in the form of lipid vesicles such as liposomes, the device is useful as vectors for targeting the delivery of therapeutic molecules of interest towards specific cell types, specific tissue types or specific organs (See Brisson, [0317]-[0318]).
Regarding an EV such as an exosome having a lipid on the outer surface of the EV such as PS, as discussed supra, Brisson teaches that the lipid layer is selected from: (ai) a lipid bi-layer including a lipid bi-layer coating a solid substrate, (aii) a lipid mono-layer including a lipid monolayer formed at the interface between air and an aqueous solution, and (aiii) a liposome in an aqueous solution including a liposome consisting of a vesicle with one or more lipid bi-layers enclosing an aqueous core (See Brisson, [0025]-[0028]). Brisson defines a lipid layer as a layer comprising lipid molecules where the layer has a negative net charge in an aqueous solution at a neutral pH (See Brisson, [0174]). The lipid layer comprises one or more kinds of compound that impart a negative net charge in an aqueous solution at a neutral pH (See Brisson, [0174]). Compounds that impart a negative net charge in an aqueous solution at a neutral pH consist of phospholipids or phosphate-containing molecules having a negative net charge in an aqueous solution at a neutral pH (See Brisson, [0174]). Examples of phospholipids having a negative charge in an aqueous solution at a neutral pH include 1,2-dioleoyl-sn-glycero-3-phosphoserine (DOPS) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine (POPS) (See Brisson, [0180]-[0181], [0183], [0186]). Moreover, Brisson teaches that annexin, particularly annexin-A5, binds with a high affinity to such lipids that contain a phosphoserine group in the presence of calcium ions (See Brisson, [0185]). As evidenced by the PubChem reference, DOPS is a species of phosphatidylserine, i.e., a 3-sn-phashatidyl L-serine (See PubChem reference, pg. 1). Thus, the teachings of Brisson satisfy the claim limitation with respect to where the EV contains a lipid on the outer surface of the EV that binds with a PS-binding protein as recited in instant claim 1 where the lipid is a phospholipid PS as recited in instant claim 2(a). However, Brisson does not expressly teach that the lipid layer is an extracellular vesicle such as an exosome.
Ha et al. teaches that exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes (See Ha, abstract). The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles including the advantage of exosomes being non-immunogenic in nature due to similar composition as the body’s own cells (See Ha, abstract). An exosome is a “nanosphere” with a bilayered membrane ranging in size from 40 to 100 nm (See Ha, pg. 288, col. 1, last paragraph). The bilayered membrane formed of lipids (See Ha, pg. 289, 2nd col., 3rd paragraph). Table 1 lists the lipids found in exosomal compositions including sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, GM3 and phosphatidylinositol (See Ha, pg. 289, Table 1; pg. 290, col. 1, col. 1, 2nd paragraph). PS is expressed on the plasma membrane of exosomes through different types of phospholipid transportation enzymes (See Ha, pg. 290, col. 1, 2nd paragraph). PS is also involved in docking the outer proteins and allowing the signaling and fusion of the exosome to the plasma membrane (See Ha, pg. 290, col. 1, 2nd paragraph). As such, similar to the lipid layer of Brisson, exosomes have a phospholipid bilayer including a PS.
Although, Ha et al. acknowledges that liposomes and polymeric nanoparticles are the currently preferred drug delivery system where a liposome is a synthetic vesicle with a phospholipid membrane that self-assembles into various sizes and shapes in an aqueous environment, Ha et al. identifies drawbacks to these delivery systems (See Ha, pg. 290, col. 2, last paragraph). Drawbacks include the ability of a liposome to evade the host immune system with a long circulating capability, with stability, and without toxicity (See Ha, pg. 290, col. 2, last paragraph to pg. 291, col. 1, 1st paragraph). Polymeric nanoparticles may have been stability than liposomal systems, but their biocompatibility and long-term potential safety remain a concern (See Ha, pg. 291, col. 1, 1st paragraph). Conversely, exosomes have many of the desirable features of an ideal drug delivery system such as a long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent toxicity issues (See Ha, pg. 291, col. 1, 1st paragraph). More specifically, Ha et al. teaches that exosomes act as a mimic of “nature’s delivery systems” thereby allowing for delivery of biological molecules; can avoid phagocytosis or degradation by macrophages given their small size and being nature’s own cellular product; circulate for extended periods of time within the body; potentially avoid the endosomal pathway and lysosomal degradation and deliver cargo directly into the cytoplasm; are naturally stable and have inherent targeting properties; and can cross the BBB (See Ha, pg. 294, col. 1, last paragraph). Thus, Ha et al. teaches that exosomes appear to be a superior choice overcoming the limitations observed with the majority of liposomal or polymeric drug delivery systems (See Ha, pg. 291, col. 1, 1st paragraph). Therefore, an ordinary skilled artisan would be motivated to substitute the liposome of Brisson with an exosome as suggested by Ha et al. as further articulated below.
Regarding the PS-binding protein such as annexin is bound to the outer surface of the EV by covalently binding to a lipid, Brisson defines a fusion complex as a hybrid molecule that comprises an annexin protein moiety that is covalently linked to a partner molecule, notably a protein, a peptide or nucleic acid (See Brisson, [0029], [0230]). As depicted in Figure 1C, the anchoring complex is bound to a lipid on the outer surface of the liposome (See Brisson, [0058]-[0063]; Figure 1C). The annexin protein binds to lipid layers in the presence of calcium ions in a quasi-irreversible manner (See Brisson, [0158]). As such, Brisson teaches that the 2D matrices of anchoring complexes disulfide-linked annerxin-A5 dimers on lipid layers are able to anchor liposomes containing negatively charged phospholipids such as a phospholipid phosphatidylserine (as described supra) in the presence of calcium ions (See Brisson, [0161]). Brisson also teaches that the main advantageous properties of the annexin moiety of the fusion complex are the capacity of forming high-density 2D protein matrices on phospholipid surfaces and the fact that the 2D protein matrices are stably bound to the phospholipid surfaces (See Brisson, [0210]). It is also known that annexins bind with high affinity to lipid surfaces containing negatively charged phospholipids in the presence of calcium ions (See Brisson, [0211]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Brisson and utilize a device comprising (a) an exosome instead of a liposome having a phospholipid bilayer comprising phosphatidylserine compounds such as DOPS and POPS thereby giving the bilayer a negative charge in an aqueous solution at a neutral pH; and (b) a 2D matrix of anchoring complexes that are bound to a phosphatidylserine compound in the bilayer on the outer surface of the exosome, each of the anchoring complexes comprise a fusion complex comprising an annexin protein as a PS-binding protein fused to a partner molecule where the annexin protein is bound to the phosphatidylserine compound and the partner/bait molecule consists of an organic or a mineral compound such as a polypeptide or protein where substituting an exosome instead of a liposome exhibits desirable features of an ideal drug delivery system such as a long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent toxicity issues. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because exosomes were known to offer advantages over liposomes such as a long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent toxicity issues as taught by Ha et al; and because annexin proteins were known to bind with a high affinity to lipids that contain a phosphoserine group in the presence of calcium ions as taught by Brisson.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the device comprising a liposome having a phospholipid bilayer comprising phosphatidylserine compounds such as DOPS and POPS thereby giving the bilayer a negative charge in an aqueous solution at a neutral pH; and (b) a 2D matrix of anchoring complexes comprising a fusion complex comprising an annexin protein fused to a partner/bait molecule where the annexin protein is bound to the lipid layer and the partner/bait molecule consists of an organic or a mineral compound such as a polypeptide or protein of Brisson was used as vectors for targeting the delivery of therapeutic molecules of interest towards specific cell types, specific tissue types or specific organs. Therefore, substituting an exosome in place of the liposome having the phospholipid bilayer comprising PS compounds and a 2D matrix of anchoring complexes comprising a fusion complex of an annexin protein fused to a partner/bait molecule consisting of an organic or a mineral compound such as a polypeptide or protein where the annexin protein is bound to the PS compound on the outer surface of the exosome phospholipid bilayer given its high affinity for lipids that contain a phosphoserine group in the presence of calcium ions would support the exosome exhibiting desirable features of an ideal drug delivery system such as a long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent toxicity issues by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claims 8-10 and 12, with respect to where the PS-binding protein is linked to a second protein as recited in instant claim 8; with respect to where the second protein is an antibody or a cargo-binding protein as recited in instant claim 9; with respect to where the cargo-binding protein is an antibody as recited in instant claim 10; with respect to where the composition is loaded with a cargo on the surface of the EV by binding to the PS-binding protein and optionally where the cargo is an antibody as recited in instant claim 12:
As discussed supra, Brisson teaches that in the fusion complex, the annexin protein is fused to a reporter molecule where the reporter molecule is the bait molecule itself such as a bait protein or a second protein (See Brisson, [0234]-[0235], [0237]). As such, since the reporter molecule can be the bait molecule such as a bait protein or a second protein that is fused directly or indirectly to the annexin protein (i.e., a PS-binding protein), it would then follow that the reporter/bait molecule constitutes a second protein or a cargo that is bound to the PS-binding protein on the surface of the EV where the cargo is a protein as recited in instant claims 8 and 12.
Alternatively, Brisson teaches that the second protein consists of a protein having affinity for a Fc moiety of an antibody where the second protein is not the bait molecule (See Brisson, [0241]). In this case, the bait molecule may be either (i) an antibody which is directly bound on the second protein as depicted in Figure 3-Mode 2A, or (ii) a bait molecule of interest which is bound to a bait-binding intermediate molecule as depicted in Figure 3-Mode 3, notably a bait-specific antibody as depicted in Figure 3-Mode 3A (See Brisson, [0241], [0261]). As such, the teachings of Brisson encompass where the annexin protein is bound to a partner molecule/second protein such as a protein that has an affinity for a Fc moiety of an antibody, which is bound to a bait molecule such as an antibody. Given that the instant second protein is not required to be directly linked to the PS-binding protein, Brisson’s bait molecule being an antibody indirectly linked to the annexin protein constitutes where the PS-binding protein is linked to a second protein as recited in instant claim 8 where the second protein is an antibody, cargo-binding protein such as an antibody, or a cargo is an antibody as recited in instant claims 9-10 and 12. Thus, the teachings of Brisson satisfy the claim limitations as recited in instant claims 8-10 and 12.
For claim 16, it is noted that the scope encompasses where the composition of claim 1 is co-administered with or further comprises a molecule that enhances release of the EV from endosomes such as chloroquine. As such, when the enhancement molecule is co-administered with the composition constitutes where the structure of the composition is unaltered. In other words, an enhancement molecule such as chloroquine is not required to be a structural component of the composition. Rather, it can be part of the intended use of the composition, i.e., being co-administered.
Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed composition is intended to be co-administered with an enhancement molecule such as chloroquine thereby constituting the intended use of the composition, and thus, there is no structure imparted by such a use. Since the combination of Brisson and Ha et al. suggest the composition structure as recited in instant claim 1 as discussed supra, the structural limitation imparted by the “wherein” clause is met. Therefore, the combination of Brisson and Ha et al. necessarily satisfies the claim limitation as recited in instant claim 16.
For claim 32, it is noted that that the scope encompasses an intended use of the composition of claim 1. Pursuant to MPEP 2112.02, the discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02. Thus, claim 32 is interpreted as reciting one or more intended uses of the composition, i.e., (a) for purifying an EV; or (b) as a research tool, a diagnostic tool, an imaging tool, biological reference material, an experimental control and/or an experimental standard. A recitation of an intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Therefore, reciting that the composition is to be used for one of the intended uses, only excludes a prior art reference if that reference expressly teaches or suggests that the composition could not be used for one of the claimed purposes. Therefore, the teachings of Brisson satisfy the claim limitation with respect to where the composition is for (a) for purifying an EV; or (b) as a research tool, a diagnostic tool, an imaging tool, biological reference material, an experimental control and/or an experimental standard as recited in claim 32.
For claim 34, with respect to where the composition is immobilized to a solid support:
As discussed supra for claim 1, Brisson teaches that the lipid layer can be a lipid bi-layer including a lipid bi-layer coating a solid substrate, a lipid monolayer formed at the interface between air and an aqueous solution, or a liposome. Brisson also teaches that the device comprises a substrate and the lipid layer is coated on the substrate where the substrate can consist of a solid substrate such as mica, silicon, mineral glass and gold (See Brisson, [0271]-[0273]). Further, Brisson teaches a detection system for detecting the binding of a target molecule onto a bait molecule where the system comprises a plurality of devices (See Brisson, [0277]). Moreover, Brisson teaches that in the detection system, there are two distinct detection devlces that contain distinct bait proteins (See Brisson, [0279]). The detection devices can comprise the solid substrate in the form of particles that are made of the solid substrate or in the form of particles that are coated with this solid substrate (See Brisson, [0279]). The solid substrate can be in the form of a collection of solid particles such as silica particles, silica-coated particles, or glass beads that are coated with a lipid bilayer, e.g., a liposome, onto which are bound anchoring complexes (See Brisson, [0280]). As such, the teachings of Brisson encompass where the lipid layer, e.g., a liposome, is immobilized on a solid substrate that functions as a solid support. Thus, the teachings of Brisson satisfy the claim limitation as recited in instant claim 34.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 2/6/26 for claims 1-2, 8-10, 12, 16, 20, 32, and 34 as being unpatentable pursuant to 35 USC 103(a) have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s first argument, i.e., Brisson is directed to synthetic lipid layers and not natural EVs (See Applicant’s Response received on 2/6/26, pg. 24), it is found unpersuasive. It is acknowledged that Brisson teaches liposomes, lipid bilayers, and lipid monolayers as opposed to extracellular vesicles such as exosomes. However, Applicants are respectfully reminded that the rejection supra is based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references. Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed above in the 103 rejection, the teachings of Brisson and Ha are suggestive of the claim limitations as recited in instant claims 1-2, 8-10, 12, 16, 20, 32, and 34. Brisson expressly teaches a device comprising a liposome having a phospholipid bilayer comprising phosphatidylserine compounds such as DOPS and POPS and a 2D matrix of anchoring complexes comprising a fusion complex comprising an annexin protein bound to the lipid layer and fused to a partner/bait molecule. As such, Brisson teaches the instant composition except for utilizing EVs instead of liposomes. Thus, the question is whether an ordinary skilled artisan would be motivated to substitute the liposomes of Brisson with exosomes with a reasonable expectation of success. The Examiner maintains that the answer is yes in light of the teachings of Ha et al. As discussed in the rejection supra, Ha et al. expressly acknowledges that liposomes are a preferred drug delivery system, but also recognizes drawbacks to liposomes while describing advantages of exosomes over liposomes, i.e., long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent toxicity issues. As such, even though liposomes are not identical structurally to exosomes does not preclude the advantages of exosomes over liposomes suggested by Ha et al., and does not preclude the similarities shared between exosomes and liposomes including a lipid bilayer containing phosphatidylserine compounds that bind to annexins. Therefore, contrary to Applicant’s argument, an ordinary skilled artisan would have the requisite motivation to substitute exosomes for liposomes in light of the teachings of Ha et al.
In response to Applicant’s second argument, i.e., Brisson’s annexin system causes vesicle aggregation (See Applicant’s Response received on 2/6/26, pg. 24-25), it is found unpersuasive. It is noted that the features upon which applicant relies (i.e., vesicle aggregation and therapeutic EVs) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, claim 1 is directed to a composition comprising an EV comprising a PS-binding protein/peptide that is bound to the outer surface of the EV via a phospholipid phosphatidylserine. There is no limit to the PS-binding protein/peptide, there is no requirement that the EVs in the composition do not aggregate, and there is no requirement that the EVs are to be therapeutic. It is further noted that none of the rejected claims recite the G58 peptide, i.e., a GAPDH fragment, Applicants found does not cause aggregation. Plus, if full length GAPDH causes aggregation, as identified in instant [0018], then the claimed composition can also exhibit aggregated EVs because full length GAPDH is encompassed (See instant claim 2(b)). Thus, contrary to Applicant’s argument, whether Brisson’s annexin system causes vesicle aggregation does not preclude a finding of obviousness since the claimed EVs also can aggregate.
In response to Applicant’s third argument, i.e., Ha teaches away from modifying exosome surfaces (See Applicant’s Response received on 2/6/26, pg. 25), it is found unpersuasive. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In the instant case, Ha et al. expressly teaches utilizing exosomes for drug delivery purposes. Thus, it would necessarily follow that the exosomes of Ha are being modified in order to allow for drug delivery. Applicants have not provided any evidence to support their argument that the advantage of exosomes over liposomes suggested by Ha would be canceled out by the conjugation of annexin to the outer surface. Thus, this argument is merely the argument of counsel and is unsupported by evidence or declarations of those skilled in the art. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See M.P.E.P. § 2129 and § 2144.03 for a discussion of admissions as prior art. Counsel's arguments cannot take the place of objective evidence. In re Schulze, 145 USPQ 716 (CCPA 1965); In re Cole, 140 USPQ 230 (CCPA 1964); and especially In re Langer, 183 USPQ 288 (CCPA 1974). See M.P.E.P. § 716.01(c) for examples of attorney statements that are not evidence and that must be supported by an appropriate affidavit or declaration. Therefore, without evidence to the contrary, since Ha expressly describes exosomes as drug delivery vehicles thereby resulting in modified EVs distinct from natural EVs, the teachings of Ha do not teach away from modifying exosome surfaces.
In response to Applicant’s fourth and fifth arguments, i.e., there is no motivation for cargo loading via PS-binding proteins, and claims 8-10 and 12 recite features not taught in the prior art (See Applicant’s Response received on 2/6/26, pg. 25-26), they are found unpersuasive. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it is noted that the scope of claim 1 does not require cargo loading via PS-binding proteins. As such, Applicants’ fourth and fifth arguments will be construed as pertaining to claims 8-10 and 12. Applicant is respectfully reminded that claims 8-10 and 12 are not limited to where the second protein/peptide or small molecule drug is a nucleic acid-binding protein like TRBP2. In fact, Applicants elected an antibody as the second protein. Even if Brisson uses the second protein as a “bait molecule”, the intended use of the second protein taught by Brisson is not a structural requirement, and thus, not given patentable weight. It is noted that instant claim 8 encompasses any second protein or peptide. The instantly claimed second protein or peptide does not even need to be therapeutic. It appears Applicant is interpreting the scope of claims 8-10 and 12 in a narrow sense whereas the broadest reasonable interpretation of claims 8-10 and 12 is that the second protein can be any protein including any antibody. As discussed in the rejection supra, Brisson teaches that the bait molecule may be either (i) an antibody which is directly bound on the second protein as depicted in Figure 3-Mode 2A, or (ii) a bait molecule of interest which is bound to a bait-binding intermediate molecule as depicted in Figure 3-Mode 3, notably a bait-specific antibody as depicted in Figure 3-Mode 3A (See Brisson, [0241], [0261]). Therefore, contrary to Applicants’ arguments, the cited references, in particular, Brisson, teach where the annexin (i.e., PS-binding protein) is bound to a second protein such as an antibody.
In response to Applicants’ sixth and seventh arguments, i.e., claim 16 recites endosomal release molecules not taught in the cited art, and claims 32 and 34 recite EV purification not taught in the prior art (See Applicant’s Response received on 2/6/26, pg. 26), they are found unpersuasive. Applicant’s attention is directed to the “Response to Arguments” section supra for the 102(a)(1) rejection, which is incorporated herewith and will not be reiterated. The responses are similar. Briefly, the intended uses in claims 16 and 32 are not structural limitations given patentable weight; and Brisson expressly teaches immobilizing the lipid layers.
In response to Applicant’s eighth argument, i.e., the claimed invention exhibits unexpected results of the G58 peptide binding to EVs without causing aggregation (unlike annexins), high binding capacity (~1200-1400 sites per EV), and successful in vivo gene silencing (40% HTT silencing in Huntington’s disease mice) (See Applicant’s Response received on 2/6/26, pg. 26-27), it is found unpersuasive. As an initial matter, it is noted that Applicant did not provide citations or reference to the alleged unexpected results. Pursuant to MPEP 716.02(d), whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” The Federal Circuit has recognized where Applicants have provided comparative tests with the prior art and the claimed invention. See MPEP 716.02(d). Turning to the instant specification and Examples 1-12, there are specific EVs with structural requirements including specific PS-binding proteins and specific cargo that resulted in the alleged unexpected results. Given that the broadest reasonable interpretation of instant claim 1 encompasses any EV comprising any PS-binding protein and/or peptide bound to the outer EV surface via any lipid and/or any EV protein, the scope of claim 1 is not commensurate in scope with the alleged unexpected results. Furthermore, there is no indication that the specific species of EVs taught in the Examples can be extended to the claimed genus of EVs. Therefore, contrary to Applicant’s argument, the claimed invention is not commensurate in scope with the alleged unexpected results.
Accordingly, the rejection of claims 1-2, 8-10, 12, 16, 20, 32, and 34 is maintained as Applicants’ arguments are found unpersuasive.
Claims 1 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Brisson US Publication No. 2009/0226887 A1 published on September 10, 2009 (cited in the IDS received on 11/11/22) in view of Ha et al., Acta Pharma. Sinica B 6:289-296 (2016), alone or as evidenced by, “Dioleoylphosphatidylserine” PubChem, available online at https://pubchem.ncbi.nlm.nih.gov/compound/Dioleoyl-phosphatidylserine, 32 pages (2006) (hereinafter the “PubChem reference”), as applied to claim 1 above, and further in view of Hean et al. WO Publication No. 2017/203260 A1 published on November 30, 2017, as applied to claim 14.
For claim 1, please see discussion of Brisson and Ha et al. supra.
For claim 14, with respect to where the composition further comprises a release system where the release system is a polypeptide-based release system such as a cis-cleaving polypeptide-based release system comprising intein:
As discussed supra for claim 1, Brisson teaches a device comprising a lipid layer such as a liposome having a phospholipid bilayer comprising a negative phospholipid such as DOPS or POPS that is bound to an annexin protein, which is bound to a partner molecule, which can either be a bait molecule itself or is bound to a bait molecule (See Brisson Figure 3). Figure 3, Mode 3 depicts that an intermediate molecule can be used as a linker between the annexin protein and partner molecule (See Brisson, [0067]-[0078]; Figure 3). The intermediate molecule can be an intermediate protein (See Brisson, [0236], [0241]). For example, the intermediate molecule in Figure 3, Mode 3A is an IgG molecule (See Brisson, [0078]). Moreover, Brisson teaches that when the lipid layer is in the form of lipid vesicles such as liposomes, the device is useful as vectors for targeting the delivery of therapeutic molecules of interest towards specific cell types, specific tissue types or specific organs (See Brisson, [0317]-[0318]). However, Brisson does not expressly teach including a release system where the release system is a polypeptide-based release system such as a cis-cleaving polypeptide-based release system comprising intein.
Hean et al. teaches EV-based therapeutics based on exosomes or any other type of EVs comprising at least one polypeptide/protein of interest (Pol) where the Pol is released from an endogenously activatable polypeptide-based release system and subsequently delivered into a target cell (See Hean pg. 3, 1st paragraph). The release system is based on a fusion protein between an exosomal polypeptide and a domain that enables endogenously activatable releasable attachment of the Pol, meaning that the Pol may be released through an endogenous activation trigger into one or more of e.g. the lumen of an EV, into the membrane of an EV or into any compartment or organelle of a target cell or target tissue (See Hean pg. 3, 1st paragraph). As such, Hean et al. teaches EVs comprising at least one Pol wherein the at least one Pol is attached to an exosomal polypeptide via an endogenously activatable release system (See Hean, pg. 4, last paragraph; pg. 16, last paragraph). The Pol is releasably attached to an exosomal polypeptide via endogenously triggered release domain(s) or a Pol released via endogenous activation from an exosomal polypeptide that is normally inside the lumen or the membrane of the EV (See Hean, pg. 5, last paragraph). Hean also teaches that the Pol can be released onto the external side of the EV membrane or target cell (See Hean, pg. 15, 1st paragraph). The Pol being releasable enables efficient, non-obstructed loading and endogenously triggered release of the therapeutic Pol into the EV (See Hean, pg. 5, last paragraph). Hean et al. further teaches that a preferred example of a polypeptide-based release system is a cis-cleaving polypeptide-based release system, e.g., based on inteins (See Hean, pg. 16, last paragraph to pg. 17, 2nd paragraph). Thus, Hean et al. teaches EVs comprising at least one Pol wherein the at least one Pol is attached to an exosomal polypeptide via a polypeptide based release system such as a cis-cleaving polypeptide based release system comprising an intein in order to deliver the Pol into a target cell where the use of such a polypeptide based release system enables efficient, non-obstructed loading and endogenously triggered release of the therapeutic Pol into the EV.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Brisson and Ha et al. such that the exosome suggested by Brisson and Ha et al. is further modified such that an exosomal protein in the membrane of the exosome is linked to a cis-cleaving polypeptide based release system comprising an intein, which is then linked to a Pol in order to deliver a Pol into a target cell where the use of such a polypeptide based release system enables efficient, non-obstructed loading and endogenously triggered release of the therapeutic Pol into the EV. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because exosomes were known to comprise at least one Pol wherein the at least one Pol is attached to an exosomal polypeptide via a polypeptide based release system such as a cis-cleaving polypeptide based release system comprising an intein where the polypeptide based release system was known to enable efficient, non-obstructed loading and endogenously triggered release of the therapeutic Pol into the EV as taught by Hean et al.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the exosomes of Brisson and Ha et al. was used as vectors for targeting the delivery of therapeutic molecules of interest towards specific cell types, specific tissue types or specific organs, and therefore, modifying the exosome such that the exosome suggested by Brisson and Ha et al. is further modified such that an exosomal protein in the membrane of the exosome is linked to a cis-cleaving polypeptide based release system comprising an intein, which is then linked to a Pol would support the efficient, non-obstructed loading and endogenously triggered release of the therapeutic Pol into the EV by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 2/6/26 for claims 1 and 14 as being unpatentable pursuant to 35 USC 103(a) have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s first, second, third, fourth and sixth arguments, i.e., the proposed combination of references does not arrive at the claimed invention; Hean’s release system is for exosomal membrane proteins, not PS-binding proteins; there is no motivation to combine release systems with PS-binding proteins; the references address different technical problems; and claim 14’s release system is functionally connected to the PS-binding protein (See Applicant’s Response received on 2/6/26, pg. 27-29), they are found unpersuasive. It is noted that the features upon which applicant relies (i.e., the release system of claim 14 must be bound to the PS-binding protein that is bound to the outer surface of the exosome) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, Applicants assert that the release system of claim 14 must be associated with the PS-binding protein that is bound to the outer surface of the EV. The Examiner respectfully disagrees with such a limited interpretation. It is noted that claim 14 recites, “wherein the composition further comprises….” The composition of claim 1 only requires one structural component, i.e., modified EVs (See Response to Arguments section supra for the 102 rejection). However, there is no expressed limitation that requires that the release system to be associated with the PS-binding protein/peptide. Rather, the broadest reasonable interpretation of claim 14 encompasses where the release system can be associated anywhere on the EV. Arguably, in light of Applicant’s argument regarding what constitutes a “composition” supra for the 102 rejection, the release system of claim 14 does not even have to be associated with the EV of claim 1. It could be a second separate structural component of the composition. Given that the broadest reasonable interpretation of claim 14 encompasses where the release system can be associated anywhere on the EV including an exosomal membrane protein instead of the PS-binding protein, Applicants’ arguments are unpersuasive. Therefore, contrary to Applicants’ arguments, the cited combination of references render claim 14 obvious.
In response to Applicant’s fifth argument, i.e., Brisson and Hean are incompatible together (See Applicant’s Response received on 2/6/26, pg. 29), it is found unpersuasive. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). In the instant case, as discussed in the rejection supra, both Brisson and Hean describe using EVs for delivering cargo to cells. Therefore, when considering the references as a whole, an ordinary skilled artisan would be motivated to combine Brisson and Hean together to improve cargo delivery to a target.
In response to Applicant’s seventh argument, i.e., Hean’s mention of GAPDH does not support the rejection (See Applicant’s Response received on 2/6/26, pg. 29-30), it is found unpersuasive. It is noted that the features upon which applicant relies (i.e., GAPDH as a PS-binding protein) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, GAPDH is one of many possible PS-binding proteins that can be used in the claimed invention, but it is not required. The release system of claim 14 does not require GAPDH as a PS-binding protein. Therefore, contrary to Applicant’s argument, Hean’s discussion of GADPH is not dispositive as whether the combination of cited references render the claimed invention obvious.
In response to Applicant’s eighth argument, i.e., the claimed invention exhibits unexpected results (See Applicant’s Response received on 2/6/26, pg. 30), it is found unpersuasive. Applicant’s attention is directed to the “Response to Arguments” section supra for the 103(a) rejection, which is incorporated herewith and will not be reiterated. The responses are similar. Briefly, the claimed invention is not commensurate in scope with the alleged unexpected results.
Accordingly, the rejection of claims 1 and 14 is maintained as Applicants’ arguments are found unpersuasive.
Examiner’s Comment
Notwithstanding the 112 rejections supra, claim 19 is free of the prior art. The closest prior art is Gabizon et al. WO Publication No. 2008/038291 A1 published on April 3, 2008. Gabizon et al. teaches a pharmaceutical composition comprising a liposome encapsulating a cationic amphiphilic drug, and at least one lysosome/endosome pH increasing agent, and a physiologically acceptable carrier (See Gabizon, pg. 4, 2nd paragraph). The at least one lysosome/endosome pH increasing agent can be chloroquine, which enhances the cytotoxicity and/or growth inhibiting effect of a liposome encapsulated chemotherapeutic drug (See Gabizon, pg. 4, 1st paragraph). The lysosome/endosome pH increasing agent can either be encapsulated in the same liposome as the cationic amphiphilic drug, a different liposome, or be in a free, non-encapsulated form (See Gabizon, pg. 5, 6th to 8th paragraph). However, Gabizon et al. does not teach or suggest that the lysosome/endosome pH increasing agent is linked (i.e., either covalently or non-covalently) to an EV membrane-bound moiety or a PS-binding protein. Therefore, when the molecule that enhances release of the EV from endosomes is linked (i.e., covalently or non-covalently) to an EV membrane-bound moiety or a PS-binding protein, there is no teaching or suggestion in the art.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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