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 1-10, 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 Claims 21-22 and 24-26 as amended are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject matter, there being no allowable generic or linking claim.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 1-14 have been considered on the merits.
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).
In claim 1, the phrase “a pharmaceutically effective amount of mesenchymal stem cells (MSC) co-cultured with cochlear explants, a co-culture solution of mesenchymal stem cells and cochlear explants, exosomes isolated from the co-culture solution, a mesenchymal stem cell culture solution or exosomes isolated from the culture solution” is interpreted under a broadest reasonable interpretation to encompass “a pharmaceutically effective amount of” any one of:
(1) MSC co-cultured with cochlear explants,
(2) a co-culture solution of mesenchymal stem cells and cochlear explants,
(3) exosomes isolated from said co-culture solution,
(4) any MSC culture solution, or
(5) exosomes isolated from said co-culture solution (same as 3).
Note, although (1) must comprise MSC, the scope of (1) also encompasses wherein a cochlear explant(s) are present. The scope of (2) or (5) encompasses both acellular solutions, solutions comprising only MSC, and solutions comprising MSC and a cochlear explant(s). The scope of (3) encompasses exosomes produced by MSC and/or cochlear explants present in the co-culture. The scope of (4) is not limited beyond being a culture solution derived from a MSC culture and, thus, encompasses acellular solutions and solutions comprising an MSC and/or a cochlear explant(s).
In claim 2, the phrase “in a state of being spatially separated from each other” encompasses wherein the MSC and explants are plated/pipetted in separate regions of the same well or plate in a shared medium or wherein the MSC are layered on top of the explant and vice versa, i.e., in spatially different areas or regions (e.g., as in claim 3).
Claim Rejections - 35 USC § 112(a) - Written Description
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 1-14 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 what Applicant has possession of.
Claims 1-14 are directed to methods of preventing hearing loss by administering to a subject: (1) MSC co-cultured with cochlear explants, (2) a co-culture solution of mesenchymal stem cells and cochlear explants, (3) exosomes isolated from said co-culture solution, or (4) a MSC culture solution. The claims are broad in that preventing encompasses complete prevention, hearing loss encompasses any type of hearing loss, the subject can be any subject and the MSC can be any type of MSC, the administering encompasses any route of administration, and the administering can be of any MSC culture solution (e.g., monoculture or explant co-culture with or without physical separation and/or containing MSC or instead a completely acellular solution).
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 hearing loss across the full-breadth of (1) an “effective amount”, (2) any subject with hearing without further limitation, (3) co-culture without a minimum duration, (4) exosomes without size limits, or (5) without a limitation coordinating the MSC species of origin and/or the cochlear explant species of origin with the species of the subject. The specification fails to provide any composition that completely prevents hearing loss with a reasonably predictability, such as any (1) MSC cochlear explants co-culture or (2) co-culture solution derived therefrom, (3) exosomes isolated from said co-culture solution, or (4) any MSC culture solution. Thusly, the specification fails to provide an effective amount to administer for predictably achieving the aforementioned.
In its description, nowhere does the application provide a single working example for a method according to claim 1. Instead, the instant specification shows only in vitro examples wherein 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 of administering to a subject MSC co-cultures, or a co-culture solution thereof, 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.
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. The specification lacks any description of a dosage or effective amount of an MSC 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 MSC exosome composition that predictably prevents hearing loss in a subject, including ototoxic hearing loss, organ of Corti damage-induced hearing loss due to viral infection, chronic otitis media-induced hearing loss, age-related hearing loss, noise-induced hearing loss, sudden hearing loss, autoimmune hearing loss, vascular ischemic hearing loss, head injury hearing loss, or hereditary hearing loss.
The described species lacks a sufficient nexus to the breadth of the genus of any MSC, or culture solution thereof, and achieving preventing of any type of hearing loss, including in a subject not yet experiencing hearing loss. The described species also lacks a sufficient nexus to the breadth of an undetermined dosage that would be effective as recited at preventing any type of hearing loss, which at least encompasses ototoxic hearing loss, organ of Corti damage-induced hearing loss due to viral infection, chronic otitis media-induced hearing loss, age-related hearing loss, noise-induced hearing loss, sudden hearing loss, autoimmune hearing loss, vascular ischemic hearing loss, head injury hearing loss, and hereditary hearing loss.
The scope of “subject” as used in the claims encompasses at least 6,000 different species of diverse mammals, birds, and reptiles with the sense of hearing, 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.
Furthermore, 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. For example, what age subject to receive the administering to prevent a future age-related hearing loss or how to predict a subject might in the future experience a head injury, noise-induced hearing loss, sudden hearing loss, and/or vascular ischemic hearing loss such that the preventing could be said to have occurred.
The experimental data in the instant application demonstrates co-culture duration is critical to produce a protective effect on cochlear cells in the explant by showing only a 12-hour or more duration produced the effect while shorter durations of 2 hours failed (Example 4; FIG. 4). Thus, the instant specification argues against possession of a method according to claim 1 over the full scope while argue for requiring the limitation in claim 4 in all claims. The data in the instant application is also evidence for using MSC exosome of sizes around 72 nm (or at least less than 100 nm) and at a local cochlear concentration of 109-1010, but this also suggest a lack of evidence regarding exosomes of vastly different sizes, e.g., having diameters less than 40 nm or greater than 180 nm or within the range of 100-180 nm.
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.
As claim 1 requires an “effective amount” of a pharmaceutical composition(s) be administered to the subject, this asserts an effective amount of each recited administered agent or combination exists that prevents hearing loss over the full scope of the claim, e.g., regarding the subject genus, the exosome genus, unlimited co-culture times, and unlimited routes of administration. There is no working example for administering anything to a subject to accomplish prevention of hearing loss, and dosages studied in vitro do not predictability translate to in vivo, especially wherein there is no vitro assay for hearing loss. 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 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 2-14 as set explained above.
35 USC § 112(a) – Scope of Enablement
Claims 1-14 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 treating or partially preventing/delaying ototoxic drug-induced hearing loss in a mammalian subject by administering an effective amount of (1) mammalian MSC via injection into the cochlea, cochlear nerve trunk, or subarachnoid space of a mammalian subject wherein formulated in a composition suitable for injection of living mammalian MSC, (2) purified mammalian MSC-conditioned media or exosomes via injection/implantation into the cochlea wherein formulated in a composition suitable for injection/implantation into the cochlea, or (3) cochlear explant via implantation into the subject’s cochlea and formulated for such implantation (regardless of coculture or presence of MSC); the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to treat or completely prevent any subject with hearing from experiencing any type of hearing loss merely by administering to the subject by any route over the full scope of the recited culture solution(s): (2) any co-culture solution derived from a co-culture of MSC and cochlear explants and (4) any MSC culture solution.
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 animal 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.
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 hearing loss by administering to a subject: (1) MSC co-cultured with cochlear explants, (2) a co-culture solution of mesenchymal stem cells and cochlear explants, (3) exosomes isolated from said co-culture solution, or (4) a MSC culture solution. The claims are broad in that the subject can be any subject and the administering can be merely of any MSC culture solution (e.g., monoculture or explant co-culture and/or containing MSC or acellular).
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 species subject to potential hearing loss. 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). This is a broad genus without limit, potentially encompassing any administration method known in the prior art.
The level of one of ordinary skill in the art:
The level of skill required to practice all aspects of the invention to its full scope, especially to prevent hearing loss in a human subject is high, potentially requiring a medical degree.
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. 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 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.
Additionally, the prior art teaches that merely administering autologous bm-MSC to human subject had no detectable effect of sensorineural hearing loss (Lee et al., J Audiol Otol 22: 105-109 (2018) at abstract). Also, 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 would have any preventative effect on any type of hearing loss in an actual subject. It is also not predictable what would be a pharmaceutically effective amount for preventing hearing loss is for any one of (1) MSC co-cultured with cochlear explants, (2) a co-culture solution of mesenchymal stem cells and cochlear explants, (3) exosomes isolated from said co-culture solution, (4) any MSC culture solution, and/or (5) cochlear explants from said co-culture, such as for shorter co-culture times. 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.
Without evidence, it is not reasonably predictable applicant possessed the method over the full scope of claim 1, which is broad in the scopes of (1) the subject, (2) the administering, (3) hearing loss, and (4) the choice of: (i) MSC from co-culture, (ii) co-culture solution or isolated exosomes thereof, and (iii) MSC culture solution. The additional administered agent of a cochlear explant from a co-culture in claim 14 along with any of (i)-(iii) of claim 1 is similarly not enabled over the full scopes of (1) subjects, (2) unlimited administering, and (3) any type of hearing loss. However applicant is invited to furnish evidence the contrary.
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, (3) hearing loss, and (4) the choice of: (i) MSC from co-culture, (ii) co-culture solution or isolated exosomes thereof, and (iii) MSC culture solution. The additional administered agent of a cochlear explant from co-culture in claim 14 along with any of (i)-(iii) of claim 1 is similarly not enabled over the full scopes of (1) the subject, (2) the administering, (3) hearing loss.
Moreover, an “effective amount” 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 administration route [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 administered comprises MSC, cochlear explant, acellular culture solution, or concentrated/enriched MSC exosomes. By reciting “effective amount,” claim 1 admits there are amounts that may be administered which are not pharmaceutically effective and thus a definable boundary between effective and ineffective amounts. While routine experimentation may allow identification of effective amounts of a pharmaceutical to produce an outcome in a particular type of subject (e.g., patients experiencing hearing loss), one needs guidance as to what results-effective variable to look for and a general idea of a starting amount to test and then vary the amount from there. The only guidance in the instant application is to examine recipients subject’s sense of hearing generally or to look for reduced hair cell death in the cochlea. 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.
There is no guidance at all for acellular co-culture solutions, isolated exosomes, and acellular MSC culture solutions, and similarly there is no specific guidance regarding subject selection and route of administration. 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 hearing loss by administering to a subject in need thereof for all of the composition types recited in claim 1 across their full scope as well as by any means of administering and to any subject. 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.
Additionally, extensive experimentation would be required to determine how to completely prevent hearing loss, such as any type of ototoxic hearing loss, viral infection induced hearing loss, chronic otitis media-induced hearing loss, age-related hearing loss, noise-induced hearing loss, sudden hearing loss, autoimmune hearing loss, vascular ischemic hearing loss, head injury hearing loss, and hereditary hearing loss.
Extensive experimentation would be required to determine how to prepare prevention-effective co-cultures for shorter culture durations, e.g., less than 12 or 2 hours, or less than 5 or 2 minutes, etc. (see pg. 15, 1st full para.; FIG. 4). 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 exosomes are not of an MSC origin, i.e., secreted by a cochlear explant.
Extensive experimentation would be required to determine how to prevent hearing loss (either completely or partially) in any subject that might suffer hearing loss without limit, which encompasses a diverse range of subjects (thousands of species), and may never be achievable for many therein. For example, extensive experimentation would be required to determine how to prevent hearing loss in a subject lacking a cochlea, e.g., a snake or earless lizard, such as using human MSC and/or MSC exosomes from a mammalian cell co-culture. Also, extensive experimentation would be required to determine how to prevent hearing loss using amphibian MSC cocultures or exosomes thereof on a mammalian subject, such as a human patient.
Extensive experimentation would be required to determine how to prevent hearing loss (either completely or partially) by the administering encompassing any route of administration, which encompasses a diverse spectrum of routes and may never be achievable for most of them, e.g., administering MSC or MSC exosomes orally, sublingually, rectally, or via inhalation. However applicant is invited to furnish evidence the contrary.
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.
Claim Rejections - 35 USC § 112(b)
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 3-4 and 6-7 are 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 3 recites the trademark/trade name “transwell.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name TRANSWELL® is used to describe culture chambers adapted for co-culturing cells, the description is indefinite.
Claim 4 recites “the co-culture is performed for 12 hours or more”; however, it is ambiguous and unclear as to what co-culturing step this refers to from among: (1) MSC co-cultured with cochlear explants and (2) a co-culture solution of MSC and cochlear explants.
Claim 6 recites wherein expression of HSP70 protein “increases” in the mesenchymal stem cells co-cultured with cochlear explants; however it is ambiguous, incoherent, and unclear as to what increases is being compared to. 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.
Claim 7 recites “protect inner hair cells and outer hair cells of cochlea from damage” when there is insufficient antecedent bases for any inner or outer hair cells present in the method. Is the administering to a subject having a cochlea comprising both inner and outer hair cells? Does the administering requiring contacting these cells with the administered agent?
Claim Rejections - 35 USC § 112(d)
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.
Claims 6-7 and 9-13 are 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 6 recites wherein “expression of HSP70 protein increases in the mesenchymal stem cells co-cultured with cochlear explants” but no active step is modified or added to the method of claim 1. Thus, performing the method of claim 1 is indicated by the claim language as not needing any modification to achieve the result recited in claim 6.
Claim 7 recites whereby the administered item or method as a whole results in this effect: “protect inner hair cells and outer hair cells of cochlea from damage.” However no active step is modified or added to the method of claim 1. Thus, performing the method of claim 1 is indicated by the claim language as not needing any modification to achieve the results recited in claim 7.
Claims 9-13 each recites specific features of the hearing loss conditions which are being prevented by the method of claim 1. However no active step is modified or added to the method of claim 1. Thus, performing the method of claim 1 is indicated by the claim language as not needing any modification to achieve the results recited in each of claims 9-13. For example, the method of claim 1 may be performed on any subject and then such a recipient subject would inherently be at least partially prevented in a future from an expected hearing loss due to any of the hearing loss conditions recited, including due to a future experience of ototoxic agent exposure, viral infection, aging, head injury, etc., such as wherein the sensorineural hearing loss comprises damage to inner or outer hair cells or any of their surrounding tissues.
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.
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 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.
Claims 1, 6-7, and 9-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bas (Bas et al., Stem Cells and Development 23(5): 502-14 (2014); IDS ref.).
Regarding claim 1, Bas discloses a method comprising administering a pharmaceutically effective amount of a mesenchymal stem cell (MSC) culture solution to a cochlea of a subject (MSC adoptive cell therapy for cochlear engraftment) in order to repair a damaged cochlea, e.g., support/restore cochlear neurons by promoting spiral ganglion survival and cochlear neuron replacement (pg. 511, right col., 3rd para.; pg. 512, left col., last para.; pg. 507, left col., 2nd para., to right col., 1st para.). Although Bas does not disclose this will prevent hearing loss, the preamble “intended use” language “for preventing hearing loss” does not imply any additional limitation not recited in the claim. See MPEP 2111.02.II. For purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims (see Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999) as “it is important not to import into a claim limitations that are not part of the claim.” As all the active method steps are disclosed by Bas, the method of claim 1 is anticipated.
Bas anticipates claims 6 and 7 by virtue of anticipating claim 1 as set forth above. For purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims. Although Bas does not expressly disclose the solution has an increased level of HSP70 protein, Bas discloses identical method steps to claim 1 and, thusly, the recited effect inherently occurs by performing the method of the prior art. Similarly, although Bas does not expressly disclose the intended result of protecting cochlear inner hair cells and outer hair cells from damage, Bas discloses identical method steps to claim 1 and, thusly, the recited effect inherently occurs by performing the method disclosed by Bas.
Regarding claims 9-13, Bas discloses uses for wherein the subject (e.g., a rat or other intact animal model) suffers from already ongoing hearing loss comprising a sensorineural hearing loss (due to gentamicin lesion) comprising ototoxic hearing loss caused by the drug gentamicin (Fig. 3-4; pg. 504, right col., last para., to pg. 505, left col., 1st para.), which causes damage to hair cells, ganglion neurons and/or surrounding tissues (pg. 507, left col., last para.; pg. 504, right col., last para., to pg. 505, left col., 1st para.). Thus, Bas anticipates the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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 1, 5-7, and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Long (WO2020132161, published 2020-06-25; IDS ref.) 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 a therapeutically effective amount of a pharmaceutical composition comprising a mesenchymal stem cell culture solution comprising extracellular vesicles 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]), such as a subject receiving or prescribed an ototoxoic compound, including cisplatin ([0018]).
Regarding claim 5, Long teaches wherein the MSC are derived from fat (adipose-derived), bone marrow, or cord blood ([0015]; [0072]).
Regarding claims 6-7, Long teaches the subject matter of claims 6-7 by virtue of rendering obvious claim 1. For purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims. See MPEP 2111.02. Furthermore, Long teaches wherein the administered composition comprises HSP70 protein (heat shock protein 70) ([0069]).
Regarding claims 9-13, Long teaches wherein the hearing loss comprises a sensorineural hearing loss comprising ototoxic hearing loss caused by the drug cisplatin (Example 1; [0018]), which causes damage to cochlear hair cells as evidenced by Kaur (Fig. 2).
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.
Claim 1-12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Long as applied above, and further in view of Samsung (KR 10-2018313B1; IDS ref.).
Regarding claims 2-3, Long does not teach co-culturing MSC and cochlear explants, such as in a spatially separated manner, e.g., in a Transwell® format.
However Samsung teaches co-culturing stem cells (MSC) with a patient derived cell(s) 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]; [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]).
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.
Regarding claim 4, 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]).
Regarding claim 8, Long teaches administering isolated exosomes having a size of 40-100 nm ([0035]; [0062]; [0050]). Note, a prima facie case of obviousness exists where claimed ranges overlap ranges disclosed in the prior art (MPEP 2144.05).
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]). 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 cochlear implantation of the already MSC conditioned medium-treated explant showing evidence of increased cell viability in order to increase the efficacy of a treatment to prevent new hearing loss in a subject suffering from noise-induced hearing loss.
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.
Conclusion
No claim is allowed.
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
/KEVIN K HILL/Primary Examiner, Art Unit 1638