DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status and Election
The amendments and remarks filed 6/25/26 in response to the office action of 3/25/26 are acknowledged and have been entered.
Claims 1, 7, 9, 11-12, 21, 36, 39, 45, 48, 53, 54, 57, 59, 64, 73, 78, and 79 are pending.
Claims 13 and 76 are canceled. Claims 1, 7, 21, 39, 53, 73, and 79 are amended.
Examination on the merits commences on claims 1, 7, 9, 11-12, 21, 36, 39, 45, 48, 53, 54, 57, 59, 64, 73, 78, and 79.
35 USC § 103 and 35 USC § 112b rejections of record are maintained.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(b) - maintained
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7, 9, 11-12, 21, 36, 39, 45, 48, 53, 54, 57, 59, 64, 73, 78, and 79 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 1 recites osmolarity in units of mOsm/kg. However, the term "osmolarity”, pertaining to being “at least 310 to about 450mOsm/kg" in claim 1 is unclear as osmolarity is defined as Osm/L, thus per liter (L), while claim 1 indicates the osmoles per kg, which is known for indicating the osmolality. Creedon of record teaches that in biologic systems, osmolality is expressed as mOsm/kg of water. Osmolarity is the concentration of osmoles in a volume of solvent and in biologic systems is expressed as mOsm/L of water (pg 263 col 2 para 2; Creedon (Creedon, Jamie M. Burkitt. "Sodium disorders." Small animal critical care medicine. WB Saunders, 2015. 263-268.).
Claims 7, 9, 11-12, 21, 36, 39, 45, 48, 53, 54, 57, 59, 64, 73, 78, and 79 are also rejected under 35 USC 112 (b) by virtue of their dependency on claim 1 without remedying the indefiniteness.
Claim Interpretation
Claim 1 recites osmolarity in units of mOsm/kg. Although osmolality, not osmolarity, is described by mOsm/kg, Examiner is interpreting osmolarity and osmolality as interchangeable in this case given the physiologic difference of osmolarity and osmolality are nearly identical and the terms are commonly used interchangeably in the art.
Claim Rejections - 35 USC § 103 – modified maintained
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 7, 9, 11-12, 21, 36, 39, 45, 48, 53, 54, 57, 59, 64, 73, 78, and 79 is/are rejected under 35 U.S.C. 103 as being unpatentable over Burzyn (Burzyn, D., WO2021030776A1, published January 2021), applied to claim 1, in view of RMBIO (RMBIO PBS parameters, https://rmbio.com/products/phosphate-buffered-saline-pbs#:~:text=Buffered%20saline%20solutions%20are%20balanced,such%20as%20serum%20or%20trypsin, retrieved 3/13/26, printed as pages 1/1 to 1/4, 2026) and Kelvin (Kelvin, N.G., AU-2019270977-A1).
Regarding claim 1, Burzyn discloses (Burzyn, [0622], claim 24, 136; figures 2A, 26B-D; examples 4, 15): An extracellular vesicle for treating conditions like lymphoma or other cancer types, comprising an antisense oligonucleotide (ASO) which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within a STAT6 transcript. Example 4 discloses ASO Loading on exosomes [0713] wherein ASOs targeting STAT6 were loaded onto exosomes that overexpressed PTGFRN as shown in FIG.2A. For intravenous applications carriers are disclosed like physiological saline and phosphate buffered saline (PBS) [0622]. Example 15 discloses that mice treated with exo-STAT-6 ASO had improved survival relative to PBS and exo-Scramble controls (FIGs.26B-26D). Therefore exo-STAT6-ASOs in PBS are disclosed in Burzyn.
RMBIO teaches PBS, phosphate buffered saline, is a commonly known buffer with the following well known features: a known osmolality of 279~309 mOsm/kg, pH of 7.1~7.3 and comprising NaCI (approx 137mM), KCI (approx 2.7mM), Na₂HPO₄ (approx. 10mM) and KH₂PO₄ (approx. 1.8mM) (RMBIO pg 3).
Regarding carrier and buffers for administration, storage, and stabilization of the EV ASO compositions, Burzyn further teaches acceptable stabilizer carriers, excipients, or stabilizers are nontoxic to recipients (e.g., animals or humans) at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). [0620] Examples of carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Burzyn teaches use of such media and compounds for pharmaceutically active substances is well known in the art [0619]. Although Burzyn teaches a variety of stabilizing solutions for the ASO containing extracellular vesicles such as PBS which is known to contain sodium chloride, potassium phosphate, and sodium phosphate at an osmolarity 279~309 mOsm/kg (RMBIO pg 3) as well as stabilizing solutions containing saccharides, as described above, Burzyn does not specify a storage buffer which has an osmolarity at least greater than 310 mOsm/kg to about 450 mOsm/kg.
However, Kelvin teaches the extraction and collection of cell-derived materials for therapeutic administration, including exosomes and microvesicles, using a "hypertonic solutions" formulated to a total osmolality of >350 mOsm/kg in a method that leverages hyperosmotic pressure to prompt cells such as mesenchymal stem cells to shed EVs while maintaining cell attachment and viability (pg 1, line 20-30). Kelvin teaches increasing hypertonicities of EV solutions increases EV yield (pg 2, line 15-20). Kelvin further teaches such EV carrying payloads of various oligonucleotides including ASOs (pg 9, lines 25-30).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the EV/ASO solutions employed by Burzyn to optimize osmolarity/osmolality of the storage solutions. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation of advantages of hypertonic solutions with slightly higher osmolarity than PBS because Kelvin teaches advantages of hypertonic solutions for EV/ASO cargo in the claimed osmolarity range. The skilled artisan would be motivated to optimize the osmolarity of the EV storage solutions to enhance composition efficacy in their therapeutic method.
Examiner further notes, given the advantages of optimizing storage solutions disclosed by Kelvin, that the optimization of doses/concentrations (i.e., pH, pI, conductivity, sucrose, NACL, KPO4, NAPO4) would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A.
Regarding claim 7, Burzyn teaches exosomes resuspended in a minimal volume of PBS (~200 µL) and stored at 4°C until ready to be used [0710]. Examiner interprets storage in PBS as at least 24 hours.
Regarding claim 9, the composition of the storage and administration buffers such as PBS has a pH of 7.1~7.3 , i.e. about 7.4 (RMBIO pg 3).
Regarding claims 11, 21, and 39 and the carrier/buffers for administration and storage of the EV ASO compositions, Burzyn teaches many acceptable carriers, excipients, or stabilizers are nontoxic to recipients (e.g., animals or humans) at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Examples of carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Burzyn teaches the use of such media and compounds for pharmaceutically active substances is well known in the art [0619-0620].
Burzyn does not specify the specific parameters of the storage and administration buffers of the EV/ASO composition buffers, parameters such as the specific pI (isoelectric point), conductivity, or buffer concentrations, etc. However, Examiner notes, as described above, Kelvin discloses advantages of optimizing storage buffers such that optimization of doses/concentrations (i.e., pH, pI, conductivity, sucrose, NACL, KPO4, NAPO4) would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A. Therefore, claims 11, 21, and 39 are obvious and properly rejected under 35 U.S.C. 103.
Regarding claim 12, and the pharmaceutical buffers for stabilization disclosed by Burzyn [0619-0622] to facilitate optimized storage and delivery of the ASO containing EVs, Examiner interprets these buffers as anticipating elements i-vi of claim 12 absent evidence to the contrary, i.e. wherein the composition has (i) reduced aggregates, (ii) improved stability of the EV, (iii) improved integrity of the EV architecture, (iv) improved stability of engineered proteins contained on or in EVs, (v) improved filterability, and (vi) reduced dissociation of the ASO.
Regarding claim 36, the EV/ASO storage buffers such as PBS are in a liquid solution state, i.e. non-lyophilized.
Regarding claims 45 and 64, Burzyn teaches exosome protein scaffold moieties such as PTGFRN protein Fragment scaffolds [0461].
Regarding claim 48, Burzyn teaches a scaffold protein linker [0504].
Regarding claims 53 and 54, Burzyn teaches exosome protein scaffold moieties such as PTGFRN protein Fragment scaffolds with SEQ ID NO: 301 100% identical to instant SEQ ID NO: 6 [0468].
Regarding claim 57, Burzyn teaches ASOs of the invention include antiSTAT6 ASO SEQ ID NO: 91 with 100% identity to instant SEQ ID NO: 91 [0189].
Regarding claim 59, Burzyn teaches ASOs of the invention include antiSTAT6 ASO SEQ ID NO: 91 with 100% identity to instant SEQ ID NO: 91 [0189]. Burzyn further teaches the stabilizing buffer solutions described above. Examiner again notes that the optimization of doses/concentrations of buffers are obvious based on routine experimentation, as described in the paragraph above.
Regarding claim 73, 78, and 79, Burzyn teaches exosomes, comprising an antisense oligonucleotide (ASO), wherein the ASO comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within a STAT6 transcript and wherein the exosome/ASOs are comprised within methods for producing the exosomes and methods for using the exosomes to treat and/or prevent diseases or disorders (abstract). Buffer solutions for injection and storage carrying the EVs of the invention include PBS (phosphate buffered saline) which contains a salt [0622].
Response to Arguments
Applicant’s amendments to claims 1, 7, 21, 39, 53, 73, and 79 with cancelled claims 13 and 76 are sufficient to overcome 35 USC §§ 112d, 112a, and 102(a)(1) rejections of record. However, Applicant’s arguments in the Remark (pgs 8-10) are drawn to the previous §103 rejection of record, and amendments to claim 1 further limiting the composition to at least 310 mOsm/kg necessitate a modified §103 rejection. Applicants argue that given the claims as newly amended, Burzyn offers no suggestion that changing the osmolarity/osmolality of its composition could produce any beneficial or predictable results, nor does the reference disclose a motivation for a POSA to experiment with that parameter. Applicants argue that in the absence of such recognition, any assertion that the adjustment would have been obvious lacks the necessary factual support. Examiner notes the modified §103 rejection of record above where Kelvin et al. discloses the benefits of hypertonicity in EV solutions containing ASO payloads for enhanced composition effectiveness demonstrating sufficient motivation for a skilled artisan to modify Burzyn according to the amended claim limitations.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
