DETAILED ACTION
Claims 1-20 are currently pending.
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 (claims 1-16 and 20), and Group I species of microRNA 125b (claim 10), in the reply filed on 9/10/2026 is acknowledged.
Claims 3-9 and 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/10/2026.
Priority
Acknowledgement is made of the instant application which claims the benefit of provisional application No. 63/435,877, filed 12/29/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/8/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Enablement:
Claims 1-2, 10-16 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating or alleviating an eye disorder, does not reasonably provide enablement for a method of preventing an eye disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands, 8 USPQ2d 1400 (CAFC 1988). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue’, not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary; (2) the amount or direction or guidance presented; (3) the presence or absence of working examples; (4) the nature of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
While the person of ordinary skill in the art would have a reasonable expectation of successfully treating or alleviating an eye disorder by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds (claim 1), or by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes (claim 20), the person of ordinary skill in the art would not have a reasonable expectation of preventing an eye disorder by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds (claim 1), or by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes (claim 20). Prevention of an eye disorder, for the purpose of examination, is taken in the absolute sense. Thus, in order to prevent an eye disorder, the method would entirely stop the eye disorders in all cases at all times. The skilled artisan would view the prevention of an eye disorder as highly unlikely since all cases would not be preventable by the administration of the recited pharmaceutical compositions. Thus, it would be highly unpredictable to prevent eye disorders by administering the claimed composition. Rather, it would be more appropriate to limit the claims to a method of treating and/or alleviating the eye disorders by the administration of the claimed compositions.
Applicants have provided no direction for the claimed method to prevent eye disorders. The specification discusses relieving discomfort associated with extended computer use in human subjects, improvement to clarity of vision, improvements in visual clarity, distance and reading ability, being able to read at night for the first time in years and regaining the visibility required to drive a car, reducing the amount and frequency of using additional applications of artificial tears, assisting recovery from ocular burns, or from procedures managing ocular burns such as autolimbal or
allolimbal transplantation, treating corneal inflammation (see pages 62, 65, 67 and 73-74 and 76-77, for example). Applicants have provided no results demonstrating prevention by administration of one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds (claim 1), or by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes (claim 20). Applicants have provided no long-term results showing that all cases of eye disorders can be prevented by the administration of the recited compositions. While lack of a working embodiment cannot be a sole factor in determining enablement, the absence of substantial evidence provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have a reasonable expectation of successfully preventing all cases of eye disorders by performing the claimed methods. A method for preventing all cases of eye disorders by administering one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds (claim 1), or by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes is not enabled by the instant specification (claim 20). Accordingly, claims 1-2, 10-16 and 20 are properly rejected.
Written Description:
Claims 1-2, 10-16 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 1 as currently drafted encompasses a method of preventing all cases of eye disorders by administering one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds.
Claim 20 as currently drafted encompasses a method of preventing all cases of eye disorders by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes.
As discussed above, the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of preventing all cases of eye disorders by administering one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, and/or one or more MSC-sourced compounds.
The specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of preventing all cases of eye disorders by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more types of microRNAs are sourced from one or more mesenchymal stem cell-derived exosomes.
In the instant case the specification discusses relieving discomfort associated with extended computer use in human subjects, improvement to clarity of vision, improvements in visual clarity, distance and reading ability, being able to read at night for the first time in years and regaining the visibility required to drive a car, reducing the amount and frequency of using additional applications of artificial tears, assisting recovery from ocular burns, or from procedures managing ocular burns such as autolimbal or allolimbal transplantation, treating corneal inflammation (see pages 62, 65, 67 and 73-74 and 76-77, for example). The specification provides no results demonstrating prevention.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 10-11, 13-15 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al., (Sci. Adv. 8, eabj9617 (2022) 12 January 2022; see PTO-892) (“Zhou”), as evidenced by Samaeekia et al (Invest Ophthalmol Vis Sci., October 2018, Vol. 59, No. 12, pages 5194-5200; see PTO-892) (“Samaeekia”) and Fang et al., (Stem Cells Transl Med., 2016 Oct;5(10):1425-1439; see PTO-892)(“Fang”).
For the reasons discussed above, claims 1-2, 10-11, 13-15 and 20 are not found to be enabled for preventing an eye disorder, but rather only for treating and/or alleviating an eye disorder. The following rejection is being made over the claims in so far as they read on treating and/or alleviating an eye disorder.
Zhou is directed to treating graft-versus-host disease (GVHD)–associated dry eye disease (i.e., eye disorder is ocular graft-versus-host disease) by administering MSC-derived exosomes (MSC-exo) formulated as an eye drop solution (i.e., pharmaceutical composition). Zhou teaches establishing two dry eye mouse models and conducting a clinical study (NCT04213248) to evaluate the tolerability and efficacy of MSC-exo eye drops for treating GVHD-associated dry eye disease in patients who were refractory to currently available drugs or surgeries (page 1, right col, last paragraph).
Regarding claims 1 and 14-15, Zhou assessed the efficacy of the MSC-exo treatment using
the nonobese diabetic (NOD)–Prkdcem26Cd52 IL2rgem26Cd22 Nju (NCG)– GVHD mice, which is another well-established mouse model of GVHD-associated dry eye disease. The mice were administered 5 µl of eye drops (i.e., pharmaceutical composition) comprising an exosome concentration of 2.5 x 1010 particles/ml, twice a day for 7 days. Zhou teaches the exosomes administered to the mice were derived from mouse bone marrow mesenchymal stem cells (page 11, left col, first para). Zhou’s Fig. 2 illustrates the administered MSC-exo composition resulted in promoting recovery of the GVHD-associated dry eye disease (i.e., treating one or more symptoms of the eye disorder associated with the eye).
Zhou further assessed topical administration of MSC-exos to treat human refractory GVHD-associated dry eye disease (i.e., treating an eye disorder), wherein 14 patients were administered exosomes sourced from human umbilical cord MSCs (UC-MSC-exo). The exosome composition was formulated as eye drops (i.e., pharmaceutical composition) and dispensed at a concentration of 10 µg/50 µl and administered four times a day per eye for 2 weeks (page 3, left col, 2nd para). Zhou’s Fig. 3 illustrates the marked reduction in corneal epithelial damage, improvement of epithelial recovery detected by fluorescein staining after 14 days of MSC-Exo treatment, and more than half of the treated eyes presented with increased tear volume by Schirmer’s test. Hence, Zhou demonstrates the treatment method successfully treated one or more symptoms of the mouse and human eye disorders, thus anticipating claims 1 and 14-15.
Regarding claim 20, it is noted that Zhou teaches further investigation of the microRNA (miRNA) cargo carried by the MSC-exos, and if said miRNAs might contribute to the exosomes’ therapeutic effect. Zhou teaches that miR-204-5p is one of the most abundant miRNAs found in MSC-exos (page 4 at miR-204 is required for antixerophthalmic effect of MSC-exo; Fig. 6, A-C). Zhou teaches conducting loss-of-function experiments to assess the role of miR-204. Zhou teaches that miR-204 blockage abolished the therapeutic effects of the administered MSC-exo (page 4 at miR-204 is required for antixerophthalmic effect of MSC-exo).
Therefore, Zhou’s teaching anticipates treating or alleviating an eye disorder by administering to the eye of a subject an effective amount of a pharmaceutical composition comprising one or more types of microRNAs, wherein the one or more microRNAs are sourced from one or more mesenchymal stem cell (MSC)-derived exosomes.
Regarding claim 2, Zhou teaches the administered MSC-exo composition reprogrammed ocular surface M1 macrophages into the M2 anti-inflammatory phenotype, wherein the proportion of M1 macrophages notably decreased in mice treated with MSC-exo (see pages 3-4 at MSC-exo reprogram ocular surface M1 macrophages into M2 phenotype). Thus, Zhou’s method anticipates claim 2.
Regarding claim 10, as set forth above regarding claim 1, Zhou teaches administering exosomes derived from umbilical cord mesenchymal stem cells (UC-MSC-exo) to the human patients. Fang evidences that exosomes derived from umbilical cord mesenchymal stem cells comprise the microRNA mi-125b (Abstract).
Thus, Zhou’s teaching of administering to the eye of a subject MSC-derived exosomes anticipates claim 10.
Regarding claim 11, Zhou teaches the pharmaceutical composition is administered as an eye drop solution/suspension, thus anticipating claim 11.
Regarding claim 13, it is noted that Zhou teaches formulating the MSC-exo eye drops according to reference 26, i.e., Samaeekia et al (see PTO-892). Samaeekia et al evidences the exosomes are formulated by resuspension in PBS (phosphate buffered saline) (see Isolation of Exosomes at page 5195). Thus, Zhou’s teaching anticipates claim 13.
Claim(s) 1, 11, 13, 15 and 20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Tomarev et al., (US Patent No. 11,058,729; IDS 12/18/2023) (“Tomarev”).
For the reasons discussed above, claims xxxx are not found to be enabled for preventing an eye disorder, but rather only for treating and/or alleviating an eye disorder. The following rejection is being made over the claims in so far as they read on treating and/or alleviating an eye disorder.
Tomarev is directed to methods for treating glaucoma using exosomes and/or miRNA (Abstract).
Regarding claims 1, 11 and 13, Tomarev teaches administering to a subject having glaucoma, a therapeutically effective amount of exosomes from mesenchymal stem cells, such as bone marrow stem cells ([0006], [0088]). Tomarev further teaches the disclosed methods include selecting a subject with glaucoma and administering to the subject a therapeutically effective amount of exosomes and/or a miRNA and/or a nucleic acid encoding at least one miRNA locally to the eye, e.g., to the vitreous of the eye, as well as systemic administration, intravenous, intraperitoneal, or subcutaneous administration ([0089]), wherein the therapeutically effective amount of any of the disclosed therapeutic agents can be suspended in a pharmaceutically acceptable carrier, for example, in an isotonic buffer solution ([0090]). Tomarev teaches intravitreal injection of the therapeutic exosomes, one or more miRNAs, a nucleic acid encoding a miRNA, or a vector, can be performed once, or can be performed repeatedly, such 10 times, can be performed biweekly, weekly, every other week, monthly, or every 2, 3, 4, 5, or 6 months ([0094]).
Tomarev, at [0255]-[0256] and [0259]-[0260], specifically discloses in vivo treatment for optical nerve crush (ONC) (i.e., an eye disorder) according to the experimental design shown in FIG. 8, wherein 36 adult rats were divided into the following 6 groups:
Group 1, uninjured/untreated;
Group 2, ONC/untreated;
Group 3, ONC/BMSC-derived exosomes;
Group 4, ONC/fibroblast-derived exosomes;
Group 5, ONC/SiAgo2 transfected BMSC-derived exosomes;
Group 6, ONC/SiScrambled transfected BMSC-derived exosomes.
Only 1 eye per animal was used. ONC was performed on day 0 contemporaneously with baseline recordings of electroretinography (ERG)/optical coherence tomography (OCT). BMSC-derived exosomes were administered intravitreally by Hamilton syringe on day 0, 7 and 14, delivering 3 x 109 exosomes /5 µl PBS solution (i.e., administered as a solution, a pharmaceutically acceptable carrier, claims 11 and 13), and animals were sacrificed on day 21 following ERG/OCT measurements.
Tomarev teaches treatment with the BMSC-derived exosomes preserved RNFL thickness following ONC, i.e., treating an eye disorder ([0281]).
Hence, Tomarev anticipates claims 1, 11 and 13.
Regarding claim 15, Tomarev, at [0255]-[0256] and [0259]-[0260], discussed immediately above, specifically discloses in vivo treatment for optical nerve crush (ONC), i.e., injury to eye associated structures.
Additionally, Tomarev at Example 17 discloses a mouse model of glaucoma treatment, specifically pigmentary glaucoma, wherein Example 17 discloses intravitreally administering BMSC-derived exosomes in a 2 µl solution of PBS at a concentration of 1 x 109, wherein injections were performed once a month, from 3 to 12 months ([0306] and [0313]). Tomarev, at [0334], teaches the results acknowledge that the administered exosomes protect RBPMS+ RGCs from death and the number of degenerating axons in the optic nerve was also significantly diminished after BMSC sEV treatment.
Hence, Tomarev’s teachings anticipate claim 15.
Regarding claim 20, Example 18 of Tomarev discloses administering MSC-derived microRNA (miR-26a, miR-17, miR-30c-2, miR92a, miR-292, and miR-182) for promoting retinal ganglion cell (RGC) survival after optic nerve crush (ONC) injury. The candidate miRNAs were selected based on their abundance in the neuroprotective BMSC-derived exosomes. Thus, Tomarev’s teaching anticipates claim 20.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou, as evidenced by Samaeekia and Fang, as applied to claims 1-2, 10-11, 13-15 and 20, and further in view of Lin et al., (Clinical Ophthalmology, 3 July 2015, pages 1209-1213; see PTO-892) (“Lin”).
The teaching of Zhou, as evidenced by Samaeekia and Fang is set forth above.
Regarding claims 12 and 16, it is noted that Zhou does not further teach the MSC-exo composition is administered in with one or more additional agents (claim 12) or in conjunction with one or more therapeutic, prophylactic, and /or diagnostic agents (claim 16). However, Lin is directed to ocular manifestations of graft-versus-host disease and teaches that, when topical anti-inflammatory drops were used in addition to tears, 54.3% of patients’ ocular symptoms stabilized (Abstract, Results; page 1211 left col, first para). Lin teaches anti-inflammatory therapy and autologous serum offer significant improvement over tears alone (page 1212, right col, last para to page 1213, left col, first sentence). Hence, Lin has established that topical anti-inflammatory drops provide beneficial treatment for ocular GVHD.
Therefore, it is submitted that because each of the therapeutic compositions disclosed by Zhou and Lin were known to individually treat ocular symptoms in those suffering from ocular GVHD, it would further have been obvious to one having ordinary skill in the art to combine the MSC-exo composition of Zhou with the anti-inflammatory composition of Lin for the purpose of producing a composition that is effective in reducing the ocular symptoms that accompany ocular GVHD. Combination of multiple products each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The person of ordinary skill in the art would have been motivated to modify the composition of Zhou to include an anti-inflammatory agent, as taught by Lin, for the predictable result of successfully promoting ameliorating ocular symptoms associated with ocular GVHD, thus meeting the limitation of claims 12 and 16.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Zhou and Lin because each of these teachings are directed at treating ocular GVHD.
Claim(s) 2, 12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Tomarev, as applied to claims 1, 11, 13, 15 and 20 above, as evidenced by Zhou (set forth above).
Tomarev is set forth above.
Regarding claim 2, Tomarev does not specifically comment on the administration of the therapeutic MSC-derived exosomes resulting in altering one or more responses of one or more immune cells in the subject, and wherein the one or more immune cells are selected from those recited in claim 2.
However, it is submitted that Tomarev teaches administering exosomes derived from bone marrow-derived MSCs (BM-MSC) or umbilical cord-derived MSCs (UC-MSC), as is disclosed in Applicant’s specification (page 26, lines 17-26).
Applicant’s specification (page 26, lines 17-26) discusses that UC-MSC share similar functional properties with BM-MSC but have a higher capacity for exosome (Exos) production. Therefore, absent evidence to the contrary, it is considered that Tomarev’s disclosed exosomes, derived from bone marrow-derived MSCs or umbilical cord-derived MSCs (as disclosed in the instant specification) would necessarily alter responses from one or more immune cells, as required by claim 2.
It is noted that chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure (i.e., exosomes derived from the same cell type), the properties Applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not inherently possess the same properties as instantly claimed product.
Moreover, Zhou teaches administering exosomes derived from umbilical cord MSCs, wherein said exosomes reprogrammed ocular surface M1 macrophages into the M2 anti-inflammatory phenotype, wherein the proportion of M1 macrophages notably decreased in mice treated with MSC-exo (see pages 3-4 at MSC-exo reprogram ocular surface M1 macrophages into M2 phenotype). Thus, Zhou further evidences that Tomarev’s administered exosomes, which were derived from umbilical cord MSCs, would necessarily alter one or more responses from macrophages, thus meeting the limitation of claim 2.
Regarding claims 12 and 16, it is noted that although Tomarev, at [0255]-[0256] and [0259]-[0260], does not further teach administering an additional agent, Tomarev at [0092] teaches administering a local anesthetic to the subject’s eye prior to intravitreal injection of the therapeutic exosomes and/or miRNA, as well as additional agents including antibacterial and antifungal agents, or anti-inflammatory agents ([0097]). Thus, Tomarev does render obvious administering a local anesthetic to the subject’s eye prior to intravitreal injection of the therapeutic exosomes and/or miRNA, that is, Tomarev teaches the limitations required by the current claims and as all limitations are found in one reference it is held that administering an additional agent, e.g., anesthetic, antibacterial and antifungal agents, or anti-inflammatory agents, is within the scope of the teachings of Tomarev, and thus renders the invention of claims 12 and 16 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to administer a local anesthetic to the subject’s eye prior to intravitreal injection of the therapeutic exosomes and/or miRNA, as well as additional agents including antibacterial and antifungal agents, or anti-inflammatory agents. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Tomarev.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Tomarev, as evidenced by Zhou, as applied to claims 2, 12 and 16 above, and further in view of Zhou et al., as evidenced by Fang (set forth above).
The teaching of Tomarev is set forth above.
Regarding claim 10, as set forth above, it is noted that Example 18 of Tomarev discloses administering MSC exosome-derived microRNAs, i.e., miR-26a, miR-17, miR-30c-2, miR92a, miR-292, and miR-182, for promoting retinal ganglion cell (RGC) survival after optic nerve crush (ONC) injury.
Tomarev does not further teach administering microRNA-125b. However, Tomarev does teach the MSC-derived exosomes, and their microRNA, can be derived from umbilical cord MSCs ([0106], claim 5), and Fang evidences that exosomes derived from umbilical cord mesenchymal stem cells comprise the microRNA mi-125b (Abstract).
Thus, given the administration of exosomes from umbilical cord would necessarily deliver microRNA-125b, it is submitted that Tomarev does render obvious the one or more MSC-sourced compounds comprises microRNA-125b, that is, Tomarev teaches the limitations required by the current claims and as all limitations are found in one reference it is held that administering microRNA-125b, is within the scope of the teachings of Tomarev, and thus renders the invention of claim 10 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to administer microRNA-125b to the subject’s eye. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Tomarev.
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Tomarev, as applied to claims 1, 11, 13, 15 and 20 above, and further in view of Zhou (set forth above).
Tomarev is set forth above.
Regarding claim 14, it is noted that although Tomarev teaches treating various eye disorders by administering to the eye of a subject exosomes derived from MSCs and/or miRNA derived from the MSC-derived exosomes, Tomarev does not further teach treating subjects suffering from ocular graft-versus-host disease (oGVHD).
However, as set forth above, Zhou has shown that MSC-derived exosomes are effective for treating graft-versus-host disease (GVHD)–associated dry eye disease (i.e., eye disorder is ocular graft-versus-host disease) by administering MSC-derived exosomes (MSC-exo) formulated as an eye drop solution (i.e., pharmaceutical composition). Zhou teaches establishing two dry eye mouse models and conducting a clinical study (NCT04213248) to evaluate the tolerability and efficacy of MSC-exo eye drops for treating GVHD-associated dry eye disease in patients who were refractory to currently available drugs or surgeries (page 1, right col, last paragraph).
Therefore, given that Zhou has shown successful treatment of ocular GVHD using MSC-derived exosomes, and Tomarev employs the same MSC-derived exosomes for treating various eye disorders, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include treating subjects suffering from ocular GVHD.
The person of ordinary skill in the art would have been motivated to modify the method of Tomarev to include a patient population suffering from ocular GVHD, as taught by Zhou, for the predictable result of providing therapeutic treatment to additional patient populations, thus meeting the limitation of claim 14.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Tomarev and Zhou because each of these teachings are directed at therapeutic uses of MSC-derived exosomes for treating eye disorders.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 12-13 and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18/409,746 (reference application) (“copending ‘746”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of copending ‘746 claims the following:
A method of preventing and/or treating dry eye disease, the method comprising: administering to the eye of a subject an effective amount of a tonicity solution comprising:
one or more osmoprotectants, and one or more types of mesenchymal stem cells (MSC), one or more types of MSC- derived exosomes, one or more MSC-sourced growth factors and/or immunoregulatory proteins, and/or sterile non-heated de-cellularized human amniotic fluid (D-HAF), thereby treating, alleviating, and/or preventing one or more symptoms associated with dry eye disease.
Thus, claim 1 of copending ‘746 anticipates instant claims 1 and 15.
Claim 12 of copending ‘746 reads on instant claim 12.
Claim 13 of copending ‘746 reads on instant claim 13.
Claim 14 of copending ‘746 reads on instant claim 16.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 10-13 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18/770,542 (reference application) (“copending ‘542”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of copending ‘542 claims the following:
A method of preventing and/or treating tear hyperosmolarity, the method comprising: administering to the eye of a subject an effective amount of a topical solution, the topical solution comprising: one or more types of mesenchymal stem cells (MSC), one or more types of MSC-derived exosomes, one or more MSC-sourced growth factors and/or immunoregulatory proteins, and/or sterile non-heated de-cellularized human amniotic fluid (D-HAF), thereby treating, alleviating, and/or preventing tear hyperosmolarity.
Thus, claim 1 of copending ‘542 anticipates instant claims 1 and 11
Claim 10 of copending ‘542 reads on instant claim 10.
Claim 14 of copending ‘542 reads on instant claim 12.
Claim 15 of copending ‘542 reads on instant claim 13.
Claim 16 of copending ‘542 reads on instant claim 16.
Claim 17 of copending ‘542 reads on instant claim 16.
Conclusion
No claim is allowed. No claim is free of prior art.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
