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 .
Claim Status
Claims 1, 3, 8, 12, 14, 21-22 and 24-26 are currently pending in this application.
Election/Restrictions
Applicant's election without traverse of Group I, claims 1-14, 21-22 and 24-26, in the reply filed on Oct. 20, 2025 is acknowledged. Claims 21-22 and 24-26 as amended are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject matter, there being no allowable generic or linking claim. Claims 1, 3, 8, 12, and 14 have been considered on the merits.
Status of Rejections
Status of the rejections: the previous claim rejections pursuant to 35 USC §§ 112(b), (d) and 102 are withdrawn in view of the claim amendments except as specifically maintained below for 112(d).
Claim Interpretation
In the claims, the terms “co-culture” or “co-cultured” each encompasses wherein two or more independent cells, populations of cells, or tissues merely share a single culture medium but never come into contact with each other during the entire culture period (instant pg. 12, last para., to pg. 13, 1st para., claims 2-3 and 22).
Claim Rejections - 35 USC § 112(a) - Written Description, (modified)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 8, 12, and 14 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and has possession of.
Claims 1, 3, 8, and 12 are directed to methods of preventing future ototoxic hearing loss in a mammal by administering to this mammalian subject: (1) HSP70-expressing bone marrow MSC (bm-MSC) having experienced spatially separated co-culturing with cochlear explants, or a co-culture medium solution thereof, or (2) exosomes which contain HSP70 isolated from said co-culture. The claims are broad in that preventing encompasses complete prevention, and the administering encompasses any type of injection of any formulation of the MSCs or isolated exosomes. Regarding claim 14, the administering is not limited and the specification notes that “administering” at least encompasses the routes of oral, sublingual, parenteral (for example, subcutaneous, intramuscular, intraarterial, intraperitoneal, intrathecal, or intravenous), rectal, and topical (including transdermal) administration, inhalation, and injection, or implantation of implantable devices or substances (pg. 23-24). This is a broad genus without limit, potentially encompassing any administration method known in the prior art.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide sufficient species of the genus of methods for preventing ototoxic hearing loss across the full-breadth of (1) any mammalian subject regardless of ototoxic drug exposure past or future, (2) complete prevention of hearing loss even upon eventual ototoxic drug exposure, and (3) effective preventing without a limitation regarding the injection site, formulation or exosome composition, and/or (4) coordinating the bm-MSC and cochlear explant mammalian species of origin with the mammalian species of the subject.
In its description, nowhere does the instant application provide a single working example for a method according to claim 1, so any description is prophetic. Instead, the application provides for methods applied to mouse cochlear explants ex vivo (Example 4) wherein both the anatomical injection site and formulation are irrelevant. The specification fails to describes in detail any composition capable of predictably and completely preventing all ototoxic hearing loss. The specification also fails to provide possession of any composition that partially prevents ototoxic hearing loss with a reasonably predictability, such as a (1) bm-MSC population or (2) co-culture medium solution derived therefrom, or (3) exosomes containing HSP70 isolated from said co-culture solution, such as limited in size to diameters of 40-180 nm as the instant empirical data is silent as to exosome of sizes having diameters less than 40 nm or greater than 100 nm. Thusly, the specification fails to provide any method effective amount to predictably achieve the recited preventing result in the broad subject.
The instant specification describes in vitro examples wherein human bone-marrow derived MSC and mouse cochlear explants are co-cultured for at least 12 hours resulted in protecting hair cells (IHC and OHC) from dying due to cisplatin treatment when the MSC-treatment precedes the ototoxic damage (Examples 3-4; FIG. 3-4). Alternatively, the administration of an MSC exosome preparation alone protected mouse cochlear explants from cisplatin cytotoxicity (Example 5, FIG. 5); however, this example did not involve any co-culturing and the exosomes were limited to being less than 100 nm in size (e.g., 72.4 nm) (Example 2, FIG. 2C). Thus, the experimental setups in Examples 3-5 do not model any administering to a subject only an acellular co-culture, but rather administering directly to the cochlea of a subject MSC (either before, during or after ototoxic damage) (Examples 3-4; FIG. 3A-B) or isolated and 10X-concentrated MSC exosomes prior to ototoxic damage (Example 5; FIG. 5A).
Furthermore, none of the examples demonstrate anything about hearing loss in a subject, but rather use in vitro explant cell viability as a proxy and predictor of a very complex process in an intact subject. Furthermore, the scope of subject as used in the claims encompasses at least 6,000 different species of diverse mammals, however the methods are described prophetically at the highest level of generality except for wherein mouse cochlear cells in vitro are receiving the administration of a composition derived from human MSC cultures.
The specification also fails to provide any species of a MSC co-culture solution that might reasonably alter hearing loss other than ones comprising MSC exosomes, and even in that case there is no effective amount provided for administration nor any guarantee the exosomes comprise an effective amount HSP70 protein. The specification lacks any description of a dosage or effective amount of a bmMSC co-culture solution lacking MSC that predictably improves hearing loss. More generally, the specification lacks any description of a dosage of an MSC-cochlear co-culture, MSC co-culture solution, or isolated bmMSC exosome composition that predictably prevents hearing loss in a subject, including ototoxic hearing loss in a subject receiving an ototoxic drug.
The instant application fails to describe how subjects in need of prevention of hearing loss prior to onset are identified, such as how hearing loss is predicted to occur in a subject making them a suitable candidate for being subjected to the recited method of completely preventing hearing loss before onset. The described species lacks a sufficient nexus to the breadth of the genus of achieving preventing ototoxic drug-induced hearing loss, especially in a mammal not yet experiencing hearing loss. If there was a way to ensure ototoxic drug-induced hearing loss would occur in the mammal, then the method could be applied to such a mammal and predict preventing such hearing loss. In the instant case, no model of predictive ototoxic drug-induced hearing loss was established with a method of completely preventing this inevitability using a bmMSC coculture method with reasonable predictability.
The specification also notes that “administering” at least encompasses the routes of oral, sublingual, parenteral (for example, subcutaneous, intramuscular, intraarterial, intraperitoneal, intrathecal, or intravenous), rectal, and topical (including transdermal) administration, inhalation, and injection, or implantation of implantable devices or substances (pg. 23-24). However it is unpredictable that all these routes were possessed according to claim 1. In view of the prior art, administering via implantation of MSC and/or cochlear explants directly into the subject’s cochlea and injection of MSC and/or exosomes into ear tissue is more predictable, but there is no evidence that other routes such as oral, sublingual, or inhalation can predictably get the administered agent to contact the cochlear cells.
The specification describes MSC may be administered in a dosage of 1.0×103 to 1.0×108 cells/kg body weight (pg. 23-24) without any evidence this would be effective to prevent hearing loss. The instant application is silent as to any effective amount to administer of a pharmaceutically effective co-culture solution lacking MSC or exosomes isolated from the co-culture. Thus, the written description lacks a representative number of species for the functional genus of an effective amount and methods of administering such.
The skilled artisan could not rely upon the disclosure such that the instant specification would sufficiently describe that Applicant was in possession of a composition or method having a predictable effect in the recited method for completely preventing hearing loss over the entire scope of the claims. While there is evidence that MSC therapy or MSC exosomes may benefit a subject experiencing some types of hearing loss, there is a lack of evidence in the prior art and instant application that the method of claim 1 achieves prevention of hearing loss over the full scope of the claims, including when limited by claims 3, 8, 12, and 14 as explained above.
Response to Arguments
Applicant’s remarks filed regarding the previous 112(a) rejections on pg. 5-6 of the response have been fully considered but not found persuasive.
Firstly, Applicant submits the claims are directed to a method expressly accomplishing protecting inner and outer hair cells from cochlea damaged caused by an ototoxic drug prior to exposure to the ototoxic drug (see also Response at pg. 11). Claim 1 is interpreted as encompassing wherein the mammalian subject is expected to be exposed to the ototoxic drug or is actively administered the ototoxic drug.
Applicant traverses by arguing the written description reasonably conveys possession of an invention, based on the working examples, (1) wherein the cochlear explant is from a mouse and the ototoxic drug is cisplatin and/or (2) wherein the HSP70 containing exosomes have a size less than 100 nm (~ 72.4 nm). As set forth fully above, the narrow features discussed in the remarks highlights the overbreadth of the claim features, such as regarding route of administering and cisplatin as representative of any ototoxic drug. Furthermore, a primary deficiency in the written description is a lack of a working example of preventing in an actual subject, or at least, how to adapt the in vitro methods of the Examples based solely on explant cochlear cultures to the in vivo cochlea of a subject, such as to accomplish complete prevention of hearing loss. Rather it seems, the preamble should read “protecting” a subject from ototoxic drug-induced hear loss instead of “preventing” and make clear the subject is need thereof, such as due to being presecribed an otoxoxic drug that can induce hearing loss.
35 USC § 112(a) – Scope of Enablement, (modified)
Claims 1, 3, 8, 12, and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the specification in view of the prior art is enabled for partially preventing/delaying ototoxic drug-induced hearing loss in a mammalian subject exposed to the ototoxic drug cisplatin prior administration of an effective amount of (1) HSP70-expressing bm-MSC of the same species via injection into the cochlea, cochlear nerve trunk, or subarachnoid space, (2) purified mammalian MSC-conditioned media or exosomes therein containing HSP70 via injection into the cochlea; the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to completely prevent any mammal with hearing from experiencing ototoxic drug-induced of hearing loss merely by injecting to the subject by any route in any formulation over the full scope of the claims.
The instant applicant does not reasonably provide enablement for: i) a method of preventing hearing loss in the enormously broad genus of human and non-human mammal subjects recited at a high level of generality; ii) administering via the broad genus of anatomically distinct routes recited at a high level of generality, or a pharmaceutical composition comprising nearly limitless specific formularies, such as to accomplish completely preventing hearing loss induced by any ototoxic drug.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "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 104). 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 weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The claims are directed to methods of preventing ototoxic-drug hearing loss (e.g., preemptively) by administering via injection to a mammalian subject: (1) HSP70-expressing bmMSC co-cultured with cochlear explants or (2) exosomes isolated from said co-culture solution. The claims are broad in that the mammalian subject can be any subject and the administering can be any type of injecting in any formulation and unlimited amount.
The instant specification notes that “preventing” encompasses completely preventing hear loss from occurring before any onset (pg. 4, 2nd para.; pg. 5-6). The specification notes that “subject” at least includes humans, monkeys, mice, rats, rabbits, sheep, cows, dogs, horses, and pigs (pg. 23-24). This is a broad genus of subjects encompassing thousands of diverse mammalian species subject to potential ototoxic drug-induced hearing loss.
The state of the art:
The art teaches MSC cell therapies for treating hearing loss conditions by engrafting exogenous MSC into the cochlea via administration directly to the cochlea (SV SL, ST and/or SM) or via including MSC with a cochlear implant (Kanzaki et al., Int J Mol Sci 21: 5764 (2020) at pg. 5, 3rd para.; Fig. 1; pg. 8, last para.). The art teaches MSC co-cultured with cochlear explants results in differentiation into hair cells and auditory neurons in vitro (Dufner-Almeida et al., IDS ref. at Table 1-2; pg. 524, left col., 3rd para., to right col., 4th para.). The prior art teaches injecting human various MSC into/near cochleae of mice (e.g., olfactory mucosa, bone marrow, or adipose-derived) prevented or delayed sensorineural hearing loss (Pandit et al., Stem Cells 29: 670-7 (2011) at Abstract; Bettini et al., Cytotherapy 20: 189-203 (2016); Chen et al. Int J Pediatr Otorhinolaryngol 117: 67-72 (2019); Ma et al. Am J Transl Res 8: 5235-45 (2016)) and injecting a bone marrow-derived MSC culture solution comprising human MSC into cochleae of guinea pigs deafened with the ototoxic drug neomycin promoted cochlear cell regeneration, e.g., increased the numbers of spiral ganglion neurons (SGNs) (Jang et al., Clin Exp Otorhinolaryngol 8: 83-91 (2015) at Abstract). The prior art teaches MSC paracrine effects are responsible for regimentation of damaged cochlear sensory nerves (Bettini et al., at abstract).
The prior art is silent as to oral, sublingual, or inhalation administration of MSC, such for addressing hearing loss. The art is silent as to oral, sublingual, parenteral, rectal, topical, or inhalation administration of cochlear explants. The prior art teaches MSC and their exosomes may be able to migrate to sites of tissue injuries (Chorath et al., Syst Rev 8: 126 (2019) at pg. 4729, right col., para. 3-4); however the art is silent as to migration of cochlear explants. The prior art is also silent as to administering to a subject a mixture of MSC and cochlear explant previously co-cultured in vitro in order to prevent hearing loss. However applicant is invited to furnish evidence the contrary.
Therefore, the disclosure provided by the applicant in view of prior art must encompass a wide area of knowledge to a reasonably comprehensive extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or reasonable burden being on such artisan.
The amount of direction and guidance and working examples provided by Applicant:
The instant application lacks any working example of a method according to claim 1. Instead, the instant specification shows only in vitro examples wherein bone-marrow derived MSC (bmMSC) and mouse cochlear explants are co-cultured for at least 12 hours resulted in protecting hair cells (IHC and OHC) from dying due to subsequent cisplatin treatment (Examples 3-4; FIG. 3-4). Alternatively, the administration of an MSC exosome preparation alone protected mouse cochlear explants from cisplatin cytotoxicity (Example 5, FIG. 5); however, this example did not involve any co-culturing and the exosomes were limited to being less than 100 nm in size (e.g., 72.4 nm) (Example 2, FIG. 2C).
The experimental setups in Examples 3-5 are not models of administering MSC co-cultures, or a co-culture solution thereof, but rather administering directly to the cochlea of a subject living MSC (Examples 3-4) or isolated and concentrated MSC exosomes (Example 5).
In vitro data of less hair cell cytotoxicity in a 24-48 hour period in a mouse explant is not necessarily predictive for functionally preventing hearing loss in a subject, especially when hearing loss can be caused by diverse environmental factors other than ototoxic drugs like infections, noise, autoimmune disease, and physical injury as well as other etiologies like genetic inheritance and merely normal aging. A 48-hour mouse explant model cannot take all these diverse situations into account. Thus, the method of administering anything to a subject to prevent hearing loss in the instant application is purely prophetic in nature and theoretically supported only by in vitro evidence using administration of mammalian bone marrow-MSC, or isolated exosomes thereof, to a mammalian cochlea intentionally damaged by cisplatin, and not involving a co-culture composition.
The prior art notes that site of MSC injection is critical to effectiveness in repairing ototoxic drug (ouabin) induced damage (Matsuoka et al., Larynoscope 117: 1629-35 (2007) at abstract) and that intravenous administration of MSC is unpredictable due to challenges in penetrating the blood-labyrinth barrier of the ear (Kanzaki et al., Int J Mol Sci 21: 5764 (2020) at pg. 8, last para., to pg. 9, 2nd para.).
From this empirical data, it is not necessarily predictable that administering any co-culture solution or isolated exosomes thereof (even if containing high levels of HSP70) would have any preventative effect on all types of ototoxic hearing loss in an actual mammalian subject. Although effects were demonstrated in vitro for preventing cisplatin-induced cytotoxicity in an explant model, this is not necessarily translatable to the function of hearing in a subject and is not indicative of a complete prevention of hearing loss in vivo.
Thus, neither the instant application nor the prior art describes a method enabled over the full scope of claim 1, which is broad in the scopes of (1) the subject, (2) the administering as an injection, (3) all ototoxic drug-induced hearing loss, and (4) the choice of: bmMSC from co-culture or isolated exosomes thereof.
Moreover, an effective amount for preventing is a functional property that is dependent upon many different variable parameters, including, but not limited to: the type of hearing loss being prevented [parameter 1], the type of subject [parameter 2], the anatomic injection site [parameter 3], the pharmaceutical composition (e.g., delayed release) [parameter 4], the dosage administered, i.e. totaling multiple doses via different administration events [parameter 5]; and importantly, parameter 6: whether the composition being injected comprises bmMSC or exosomes of any size. Also, the only guidance as to starting amount (or ongoing dosage) is limited to compositions with living MSC at 1.0×103 to 1.0×108 cells/kg body weight, which is a very wide range (100 million-fold) and in units that do not pharmacological scale between mammals of diverse shapes, e.g., gerbils to blue whales. This leaves the unguided skilled artisan only with the teachings of the closest prior art.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to prevent ototoxic hearing loss by administering to a mammalian subject across the full scope as well as by any means of injecting and formulation. The science of medicine has not evolved such that, without guidance or working examples in the specification for any effect occurring in a subject, the claims lack enablement for the full scope of the claimed invention. Importantly, extensive experimentation would be required to determine how to completely prevent ototoxic hearing loss, especially in a subject not yet exposed or expected to ever be exposed to an ototoxic drug. For example, extensive experimentation would be required to determine how to prepare prevention effective exosome compositions wherein the exosomes are isolated from the co-culture, including wherein the exosomes have a diameter less than 40 nm or greater than 180 nm or within the range of 40-180 nm or wherein the bmMSCs or explant (as in claim 14) is of a different species of origin from the subject.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to perform the claimed invention to prevent any hear loss in any subject using any of the compositions recited by any means of administering. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to the administering and the subject, undue and unreasonable experimentation would have been required for one skilled in the art to use the claimed methods to prevent hearing loss over the entire scope of the claims.
While no dependent claim is enabled as explained above, the claims encompass enabled subject matter in view of the prior art of a method of partially preventing or delaying ototoxic drug-induced hearing loss in a mammalian subject by, prior to ototoxic drug exposure, administering via injection or implantation into the cochlea or cochlear nerve an effective amount of mammalian MSC, a mammalian MSC-conditioned culture medium, and/or mammalian MSC exosomes derived from a cochlear explant co-culture and allowing for at least 12 hours to pass; and wherein the MSC are derived from a similar mammalian species to the subject. It is noted that claim limitations limiting (i) preventing to not encompassing “complete” or “full” prevention, (ii) hearing loss to cisplatin-induced; (iii) the administered component to comprising an effective amount of MSC and/or MSC exosomes from the recited co-culture, (iv) the administering to intracochlear injection or to a subject comprising a cochlea, and (v) when a cochlear explant is being administered, the explant being from the same species as the subject may improve the claims enablement, the vast majority of method embodiments encompassed by the instant claims lack enablement for the reasons set forth above.
Response to Arguments
Applicant’s remarks filed regarding the previous 112(a) rejections on pg. 7-10 of the response have been fully considered but not found persuasive. Applicant traverses by arguing the empirical data in the application reasonably conveys enablement based on the working examples because the in vitro explant tissue model experiments (mouse cochlear ex vivo explants) are a reliable and predictive surrogate for in vivo responses. However there is no evidence this technique is predictive for all mammalian subjects nor for injecting MSC or exosomes anywhere into the subject as the active agent (e.g., HSP70) must reach the hair cells of the cochlea according to applicant’s theory. Thus, there is a gap in delivery not addressed by the explant co-culture.
Applicant also traverses by arguing the teachings of Matsuoka are irrelevant as the claims are amended to recite “in the form of an injection,” which can bypass the blood brain barrier when the site is intracochlear or intratympanic. However this argument belays the problem, the form of injection is still not so limited. As noted above, the type of injection is relevant to enablement of the instant claims. Further, the remarks stress the claimed method produces protective effect prior to ototoxic drug exposure (e.g., Example 5), but the timing of any ototoxic drug exposure to the subject is not recited in any claim.
Claim Rejections - 35 USC § 112(b), (new)
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, 3, 8, 12, and 14 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 wherein expression of HSP70 protein “increases” in the co-culture medium compared to that in bone marrow MSCs cultured without cochlear explants,” which is incoherent, ambiguous and unclear as to how the level of a protein in a medium is being compared to its level expressed in a cell. Moreover, it is ambiguous as to whether expression of HSP70 protein increases in the exosomes isolated from the culture solution or rather if these exosomes merely must contain HP70 protein. Claims 3, 8, 12, and 14 are included in this rejection for depending from indefinite claim 1.
Claim Rejections - 35 USC § 112(d), (modified)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 recites specific species of ototoxic drug induced hearing loss conditions being prevented by the method of claim 1. However no active step is modified or added to the method of claim 1. As noted above, the claim is broad in that the subject is not required to be exposed to any ototoxic drug and the future even to be prevented need not ever occur for said subject. Claim 12 might further limit claim 1, if claim 1 provides the subject is exposed to the specific ototoxic drug(s) recited therein.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to arguments
Applicant argues that claim 12 dependency from claim 1 makes it a proper dependent claim. However, Claim 12 fails to further limit the subject matter beyond implying a subject selection step regarding future exposure to a specific ototoxic drug(s). However as noted above, the subject need never be exposed to any drug and thus this does not constitute a claim limitation of claim 1 as the claims are instantly presented.
Claim Rejections - 35 USC § 103, (modified)
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.
Claims 1, 3, 8, 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Long (WO2020132161, published 2020-06-25; IDS ref.) in view of Samsung (KR 10-2018313B1; IDS ref.) and as evidenced by Kaur (Kaur et al., J Neurosci 36: 3962-77 (2016)).
Long teaches administering (e.g., by injection into the ear or intracochlearly) to a subject (e.g., human patient or mouse) a therapeutically effective amount of a pharmaceutical composition comprising a mesenchymal stem cell culture solution comprising extracellular vesicles (e.g., of a diameter of < 150 nm) isolated from mesenchymal stem cells (MSCs) in order to prevent, delay, and/or treat hearing loss ([0006]; [0072]; Examples 1-3; [0028]; [0050]; [0052]; [0062]; [0079]; [0094]; [0096]; [0019]) wherein the MSC are derived from bone marrow ([0015]; [0072]) and wherein the subject will receiving or be prescribed an ototoxic compound capable of causing hearing loss (e.g., the drug cisplatin) (Example 1; [0018]), which causes damage to cochlear hair cells as evidenced by Kaur (Fig. 2). Long teaches wherein the administered composition comprises HSP70 protein (heat shock protein 70) ([0069]).
Regarding claim 1 and 3, although Long as evidenced by Kaur does not teach the bm-MSC exosome culture solution is from a cochlear explant co-culture or that the expression of HSP70 is increased compared to a reference culture lacking any cochlear explant, this modification of Long is obvious in view of Samsung.
Samsung teaches co-culturing bm-MSC with a patient derived cells in a Transwell® setup (e.g., to reflect all of the genetic and pathological factors of the patient and/or to evaluate efficacy at preventing/reducing cell death) and then developing the co-culture conditioned medium into a therapeutic agent for use with that specific patient ([0016]-[0017]; [0026], [0028]-[0033]; [0020]; [0049]). Samsung specifically teaches wherein the MSC are in the upper chamber and the patient test cells are in the lower chamber (FIG. 1; [0045]) for altering proteins secreted by the stem cells ([0038]-[0039]). Samsung teaches performing the co-culture for a duration over 12 hours, e.g., 5-14 days ([0031]) or 48 hours (FIG. 8-9; Example 3; [0062]; [0066]).
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to first perform the method of Samsung wherein the patient’s cells are a cochlear explant in order to test efficacy of MSC-conditioned medium and then isolate exosomes from the co-culture for administration as taught by Long. One of ordinary skill in the art would be motivated by Long teaching extracellular vesicles isolated from MSC can prevent hearing loss and Samsung teaching an in vitro test for any patient tissue using a Transwell® setup to keep the MSC physically separated from the patient’s cells in a shared medium.
Note, a prima facie case of obviousness exists where claimed ranges overlap ranges disclosed in the prior art (MPEP 2144.05). Also note, the relative HSP70 expression level need not be appreciated as it is an inherent characteristic of performing the method. Although the prior art cited above does not appreciate all the characteristics of the claimed co-culture, the characteristic of increased HSP70 expression is considered inherent. As the combination of Long and Samsung teaches all the method steps required, the recited characteristics (capabilities and potentials in an intended use) are expected to be present absent evidence to the contrary. As noted in MPEP 2112(II), it is not required that an inherent feature or property be recognized by the prior art.
Regarding claim 8, Long teaches exosome EVs are between 50-150 nm and embodiments specifically using < 150 nm exosomes, e.g., obtained by ultra-filtration ([0050]; [0094], [0062], [0069], [0124]).
Regarding claim 12, Long teaches wherein the ototoxic drug is specifically cisplatin.
Regarding claim 14, Long does not teach administering cochlear explants co-cultured with MSC along with the isolated exosomes. However Long teaches cochlear implants are a known therapeutic for noise-induced hearing loss ([0115]) and advantageous autologous transplant ([0029]). Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to combine the method taught by Long and Samsung with autologous cochlear implantation of the already bm-MSC-conditioned medium-treated explant from the same subject showing evidence of treatment (e.g., improved pathological markers) to provide the subject’s own healing cochlear cells back to the subject.
Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective time of filing in the absence of evidence to the contrary.
Response to arguments
Applicant traverses the previous 103 rejections in the response filed 6/16/26 (pg. 13-15) arguing lack of motivation to combine and unexpected results. This was not found persuasive.
Applicant argues that although Samsung teaches co-culturing patient cells with MSCs in a shared medium in physically separated manner, because their goal was to assess or assay the co-culture medium’s for therapeutic properties, Samsung does not teach this as an HSP70-priming step as part of a manufacturing process. However, Samsung clearly teaches a method of using the co-culture medium by administering it to a subject and thus is referring to some type of manufacturing process comprising the co-culture step, such as to alter the secreted protein profile, aside from a purely diagnostic method. As addressed above, although the prior art may not appreciate any increased HSP70 expression compared to bm-MSC cultured in the absence of a cochlear explant (i.e., the priming effect), this is considered inherent to performing all the active method steps recited in view of the logic of claim 1 as drafted and the laws of nature.
Furthermore, the prior art teaches bm-MSCs constitutively express heat shock protein 70 (Hsp70), albeit at a very low level, and Hsp70 is a protective against sensory hair cell death from ototoxic drug exposure (Evan et al., J Med Chem 53: 4585-602 (2010) at pg., 2nd para.; Taleb et al., Cell Stress Chaperones 14: 427-37 (2009) at Abstract). While Long teaches or enrichment of tetraspanins and heat shock protein 70). ). Long teaches wherein the exosomes are first intentionally selected for enrichment with HSP70 (heat shock protein 70) ([0069]).
While Samsung does not expressly teach using a cochlear explant, as taught by Long, the prior art teaches the goal of treating damage to cochlear hair cells, such as using a composition comprising HSP70. In the “diagnostic” setup of Samsung, it would be obvious to test against a cochlear explant tissue for signs of pathological improvement and then following through with administration to a subject.
Applicant also argues that the increased HSP70 priming results are unexpected at least in magnitude and that this is responsible for a significant protection against cisplatin-induced IHC and OHC observed ex vivo (Examples 4 and 6). The cited purported unexpected results are not commensurate in scope with the claimed invention in that the claims are not limited to any of (1) an ex vivo situation or (2) administering physically separated bmMSC allowing for shared secretory factors as in Example 4. Instead, the claimed invention requires injection either a co-culture medium or exosomes isolated therefrom to a subject to achieve a preventing of an ototoxic hearing loss. Also, as noted above, the HSP70 induction is considered inherent whether appreciated/expected or not.
Conclusion
No claim is allowed.
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 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 ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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