DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on 8/6/25 and the amendment of claims has been entered.
Election/Restrictions
Applicant's election with traverse of Group I and tumor as species of target tissue, was previously acknowledged. The requirement was deemed proper and made FINAL.
In the reply filed 1/16/25, Applicants amended claim 15 and canceled claims 17, 19, 21 and 22. Claims 1-14,16,24, 26-27, 31-84 and 86 were previously canceled.
In the reply filed 8/6/25, Applicant amended claims 15, 18 and 20. Claim 23 was canceled.
Claims 15, 18, 20, 25, 28-30, 85 and 87-89 are pending.
Claims 15, 18, 20, 25, 28-30, 85 and 87-89 are under consideration.
Claim Rejections-Withdrawn
The rejection of claims 15, 18, 20, 23, 25, 28-30, 85 and 87-89 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to amendment of the claims.
The rejection of claims 15, 18, 20, 23, 25, 28-30, 85 and 87-89 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter is withdrawn due to amendment of the claim.
The rejection of claims 18, 20 and 23 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 is withdrawn due to amendment of the claims.
Claim Objections-Withdrawn
The objection to claim 23 under 37 CFR 1.75 as being a substantial duplicate of claim 20 is withdrawn due to cancelation of claim 23.
NEW REJECTIONS
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 15, 18, 20, 25, 28-30, 85 and 87-89 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. These claims are drawn a composition comprising (i) a plurality of pain mediators including at least one interleukin, at least one growth factor, at least one protease and a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml and (ii) living neurons.
Lack of Ipsis Verbis Support
The specification is void of any literal support for the “a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml”. In the context of tumor necrosis factor, the limitation "greater than 50 ng/ml" is not present anywhere in the specification.
Lack of Implicit or Inherent Support
“While there is not in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” See MPEP 2163. Thus support can be furnished implicitly or inherently for a specifically claimed limitation. However, the specification lacks any implicit or inherent support for the claimed “a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml”. Figure 25 discloses that the TNF-alpha was tested at 50 ng/ml and 100 ng/ml. However, the disclosure of a single species (TNF-alpha) does not provide written description support for a genus of tumor necrosis factors. Additionally, the disclosure of two discrete concentration values (50 ng/ml and 100 ng/ml) does not support the claimed range encompassing all concentration greater than 50 ng/ml. Please note that the tested 50ng/ml does not meet the limitation of “greater than 50 ng/ml”.
Accordingly, the amendment introducing “a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml” constitutes new matter, as the originally filed specification does not demonstrate possession of the claimed subject matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15, 18, 20, 25, 28-30, 85 and 87-89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the osteoarthritis pain composition and concentrations of Fig. 25 (“OA soup recipe”) for stimulating a neuron to model arthritic pain, does not reasonably provide enablement for a composition comprising (i) a plurality of pain mediators including at least one interleukin, at least one growth factor, at least one protease and a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml, wherein contacting a neuron with the plurality of pain mediators stimulates the neuron to model the pain response (ii) living neurons.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As stated in MPEP 2164.01(a), “there are many 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 is “undue.”
The factors to be considered when determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, were described in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) as:
1. the nature of the invention;
2. the breadth of the claims;
3. the state of the prior art;
4. the relative skill of those in the art;
5. the predictability or unpredictability of the art;
6. the amount of direction or guidance presented [by the inventor];
7. the presence or absence of working examples; and
8. the quantity of experimentation necessary [to make and/or use the invention.
(1) The Nature of the Invention and (2) The Breadth of the claims
Claim 15 is directed to a composition comprising (i) a plurality of pain mediators including at least one interleukin, at least one growth factor, at least one protease and a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml and (ii) living neurons.
The claims will be given its broadest reasonable interpretation. The applicable rule for interpreting the claims is that “each claim must be separately analyzed and given its broadest reasonable interpretation in light of and consistent with the written description.” See MPEP 2163(II)(1), citing In re Morris, 127 F.3d 1048, 1053-1054; 44 USPQ2d 1023, 1027 (Fed. Cir. 1997). In view of this rule, Claim 15 is drawn to (i) a plurality of pain mediators including at least one interleukin, at least one growth factor, at least one protease and a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml and (ii) living neurons. The instant specification and claims do not limit the plurality of pain mediators to any specific interleukin, growth factors, protease or tumor necrosis factors or concentrations of the agents.
(3) The state of the prior art
The instant application is enabling for plurality of pain mediators identified in Figure 25 at the recited concentration for stimulating a neuron to model the arthritic pain response. However, the instant specification is not enabled for any concentration of a plurality of pain mediators comprising any interleukin, any growth factor, any protease and tumor necrosis factor, wherein contacting a neuron with the plurality of pain mediators stimulates the neuron to model the pain response.
Not all interleukins, growth factors and proteases engage pathways of nociception. For example, IL-10 suppresses inflammatory cytokines (i.e. TNF-alpha) (Clarke et al. Eur. J Immunol. 1998 May;28(5):1719-26). Furthermore, it has been shown that IL-10 reduces pain behaviors in many models (Laument et al. Pain. 2020 Oct; 161(10):2311-2352). IL-27 is disclosed as ameliorating inflammation induced pain (Alagbe et al. Blood (2025)146 (supplement 1):4709). Alagbe et al. teach that IL-27 may attenuate chronic pain by suppressing neutrophil activation, NET formation, and neuroinflammation (Abstract). Therefore, the state of the art is that the presence or expression of an interleukin does not predict induction of a pain phenotype, as multiple interleukins function primarily as suppressors of inflammatory and nociceptive signaling.
With respect to growth factors, not all growth factors are involved in inducing pain. The pain inducing effects of NGF is a specific characteristic of NGF. For example, GDNF was shown to both prevent and reverse sensory abnormalities that developed in neuropathic pain models (Boucher et al. Science 2000 Oct 6;290(5489):124-7). Boucher et al. teach the finding provide a rational basis for the use of GDNF as therapeutic treatment for neuropathic pain (Abstract).
Magnusdottir et al. (Mol Pain.2018 Oct 3;14:1744806918808161) discloses that mast cell proteases do not play a significant role in acute tissue pain (Abstract). Magnusdottir et al. state that the data indicates that mast cells are not essential to heat hypersensitivity induced by NGF (Abstract). Therefore, the state of the art is that protease activity alone does not imply nociceptive signaling or pain induction.
The state of the art is that pain phenotypes require specific molecular mechanisms that are induced by specific factors. Entire classes of interleukins, growth factors and proteases are demonstratively non-nociceptive.
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Thus, for the plurality of pain mediators stimulating the neuron to model the pain response, the possibilities are vast. The number of interleukins, growth factors, TNF’s and proteases known in the art are vast. It would be unpredictable and require undue experimentation to determine the plurality of pain mediators and the concentration of the pain mediators capable of modeling the pain response.
(4) The relative skill of those in the art and 5) The predictability or unpredictability of the art
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(6) The amount of direction or guidance presented (by the inventor) and (7) The presence or absence of working examples
The applicant provided sufficient guidance or direction regarding the potential OA pain model. Fig. 25 discloses the OA soup recipe for modeling OA pain in DRG neurons. OA soup recipe contains specific factors and specific concentrations that excited DRG neurons. Therefore, the combination of specific pain mediators and the concentration of the specific pain mediators is important in stimulating the neuron to model pain.
The instant specification fails to provide specific guidance on the specific components and concentration of other specific components that stimulate the neuron to model a pain response.
(8) The quantity of experimentation necessary (to make and/or use the invention)
Owing to the factors listed above, especially in points 6 and 7, the amount of experimentation needed will be extensive in view of the lack of guidance by the inventor.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
The instant breadth of the claim is broader than the disclosure, specifically, the instant claims are directed to a plurality of pain mediates that stimulate a neuron to model a pain response, but the specification, prior art or instant disclosure does not provide support for this.
In conclusion, the instant application is enabled for the osteoarthritis pain composition and concentrations of Fig. 25 (“OA soup recipe”), but does not reasonably provide enablement for a composition comprising (i) a plurality of pain mediators including at least one interleukin, at least one growth factor, at least one protease and a tumor necrosis factor, wherein the tumor necrosis factor is present in the composition at a concentration of greater than 50 ng/ml, wherein contacting a neuron with the plurality of pain mediators stimulates the neuron to model the pain response and (ii) living neurons.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 15, 18, 20, 23,25, 28, 85 and 89 under 35 U.S.C. 103 as being unpatentable over Johnson et al. (“In vitro models for the study of osteoarthritis” The Veterinary Journal 209(2016) 40-49) in view of Wang et al. (“Animal and cellular models of chronic pain” Advanced drug delivery reviews vol. 55, Issue 8 Aug 2003, pp 949-965) is maintained.
Johnson et al. teach both in vivo and in vitro models of OA have been used in the past (p. 40, 2nd col., last para.). Johnson et al. teach the ease of manipulating an in vitro system, as well as a shift toward the 3R philosophy of refining, reducing and replacing the use of animals in animal science makes in vitro modelling of the disease desirable (p. 40, 2nd col., last para.). Johnson et al. teach the changes in OA tissue are attributed to diffusible factors, including proteolytic enzymes, such as MMPs and member of the ADAMTS family that represent in the joint tissue during disease (p. 41, 2nd col. top para.). Johnson et al. teach models of OA off the opportunity to study early features of the development of the disease prior to the development of a fulminant catabolic process, which have bene difficult to dissect (p. 41, 1st col., 2nd para.). Johnson et al. teach during OA, synoviocytes, mononuclear cells or chondrocytes may increase their expression of catabolic proteins following stimuli such as cytokine or chemokine exposure, including IL-1beta, TNF-alpha, which are present in the joint following synovial inflammation (p. 41, 2nd col., 1st para.). Johnson et al. teach that pro-inflammatory cytokines make ideal candidates for the induction of OA-like biological changes in culture, in which temporal and concentration effects can be explored (p. 41, 2nd col., 1st para.). Johnson et al. teach models of OA where cytokines are the primary method of induction are common, generally well understood, inexpensive and very easily manipulated (p. 41, 2nd col., 2nd para.). Johnson et al. teach that IL-1beta and TNF-alpha are the most commonly used cytokines in modelling OA, other cytokines play important roles, such as IL-6, IL-8, VEGF, MCP-1 (all increased in synovial fluid of OA joints). Johnson et al. teach that exposure to IL-1beta stimulates chondrocytes and synovial cells to produce catabolic proteases with apocrine signaling further enhancing MMP release and the resulting degradation cascade (p. 41, 3rd para.). Johnson et al. teach that using cytokines in combination may allow for the induction of OA-like cell and tissue response that more closely replicate the natural disease (p. 43, 1st col., 1st para.). Johnson et al. teach that cytokine models use a variety of concentrations an durations of cytokine stimulation, namely those which produce measurable downstream effects, rather than a concentration that reflects that in natural occurring disease. Johnson et al. teach that OA is slowly progressing disease and relatively small increases in cytokine concentrations have been identified in naturally affected joints. Johnson et al. teach that when OA synovial fluid is assayed, the quantities of IL-1 and TNF are highly variable between experiments but are low in comparison to those used to exert an effect in vitro (p. 43, 1st col., 3rd para.). Johnson et al. teach the variation of physiological factors, including the method used to quantify the factors or the phenotype of the disease. Johnson et al. teach the concentration used is models are typically much higher at up to 100 ng/ml of IL-1beta and up to 50 ng/ml of TNF-alpha (p. 43, 1st col., 3rd para.). Johnson et al. teach progress in tissue engineering and cell culture techniques will allow for the development of more advanced models including other cell types. Johnson et al. teach the cross talk between different tissues in OA joints dictate that models should consider the role of multiple tissues when assessing the response to a given stimulus, to enable more meaningful translation to the anticipated response in vivo (bottom of p.45 to top of p. 46).
With respect to claim 1 (i), Johnson et al. teach IL-1beta, TNF-alpha, VEGF (growth factor) and MMP (protease) play a role in OA joint synovial inflammation. Johnson et al. does not teach the model includes (ii) living neurons. However, the teachings of Wang et al. cure this deficiency.
Wang et al. teach models of chronic pain (Abstract). Wang et al. teach primary or permanent cultures of sensory neurons have been established to study the molecular mechanism of pain (Abstract). Wang et al. teach studying pain mechanism in cell lines is an expanding area, however a number of studies have demonstrated the power to such models in elucidating mechanism and neurotransmitter release and signal transduction in pain (last para. of Introduction). Wang et al. teach that cell lines are useful for studying the molecular and cellular mechanisms of both acute and chronic pain. Wang et al. teach that when applying appropriate stimuli (i.e. pain mediator chemicals, low pH, heat) and relevant measurement endpoints, cellular models may mimic certain aspects of in vivo signal transduction between cells. Wang et al. teach that most studies utilized primary sensory neurons (para. 5-Cellular Models). Wang et al. teach sensory neurons can be isolated and cultured from different animal species and they show similar properties to hose of in vivo sensory neurons. Wang et al. teach that the cultures have been found to be valuable for studying pain neurotransmitter release, elucidating signal transduction and identifying pain mediators (para. 5.1. Primary culture of sensory neurons). Wang et al. teach permanent sensory neuron cultures as well (para. 5.2. Permanent sensory neuron cultures).
With response to claim 1 (ii), It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to create a model of OA pain using a plurality of pain mediators as taught by Johnson et al. and include neurons as taught by Wang et al. A person of ordinary skill in the art would have a motivation to include a living neuron because Wang et al. teach that the cultures have been found to be valuable for studying pain neurotransmitter release, elucidating signal transduction and identifying pain mediators. Furthermore, it would obvious to include neurons in the culture because Johnson et al. teach the cross talk between different tissues in OA joints dictate that models should consider the role of multiple tissues when assessing the response to a given stimulus, to enable more meaningful translation to the anticipated response in vivo. There is a reasonable expectation of success given that Johnson et al. and Wang et al. teach culture models of pain using pain mediators and neurons.
With respect to the new limitation “tumor necrosis factor present in the composition at a concentration greater than 50 ng/ml”, Johnson et al. teach that OA is slowly progressing disease and relatively small increases in cytokine concentrations have been identified in naturally affected joints. Johnson et al. teach that when OA synovial fluid is assayed, the quantities of IL-1 and TNF are highly variable between experiments but are low in comparison to those used to exert an effect in vitro (p. 43, 1st col., 3rd para.). Johnson et al. teach variation of physiological factors, including the method used to quantify the factors or the phenotype of the disease. Johnson et al. teach the concentration used is models are typically much higher at up to 100 ng/ml of IL-1beta and up to 50 ng/ml of TNF-alpha (p. 43, 1st col., 3rd para.). The concentration of the pain mediators is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In the instant case, Johnson et al. teach the concentration used is models are typically much higher at up to 100 ng/ml of IL-1beta and up to 50 ng/ml of TNF-alpha (p. 43, 1st col., 3rd para.). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the concentration of the plurality of pain mediators to arrive at the concentration that elicits a response in the model. Furthermore, the claimed concentration of TNF encompasses values that are numerically close to the disclosed range Optimization of such a result-driven variable would have been within the level of ordinary skill in the art. MPEP 2144.05 states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” In the instant case, the claimed concentration encompasses concentrations that are only incrementally higher than the upper limit of the prior art.
With respect to claims 18, 20, 23, 85 and 89, as evidenced by the instant specification ([PGPUB0033] and Fig. 22 and 25), synovial fluid from an arthritic knee includes claimed components. It would be obvious to include them in the culture model of OA made obvious by Johnson et al. and Wang et al. in order to model OA pain since they are found in the synovial fluid of an arthritic knee. There is a reasonable expectation of success given that the Johnson et al. teach an OA culture model including pain mediators.
With respect to claim 25, as evidenced by the instant specification, TNFα triggers a signal transduction cascade [0159].
With respect to claim 28, the limitation “are provided in media ex vivo” is interpreted as intended use. Please note that it is regarded that the "intended use" of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In Re Hack 114, USPQ 161 and do not add significantly more to the claim 15.
The rejection of claims 15, 18, 20, 23,25, 28, 85 and 87-89 under 35 U.S.C. 103 as being unpatentable over Johnson et al. (“In vitro models for the study of osteoarthritis” The Veterinary Journal 209(2016) 40-49) and Wang et al. (“Animal and cellular models of chronic pain” Advanced drug delivery reviews vol. 55, Issue 8 Aug 2003, pp 949-965) in view of Thermo Fisher Scientific-Cell culture dishes (<https://www.thermofisher.com/us/en/home/life-science/cell-culture/cell-culture-plastics/cell-culture-dishes-multidishes.html> 9/24/2015) is maintained.
The teachings of Johnson et al. and Wang et al. are presented in detail above. The references do not teach the composition is in a container. However, the teachings of Thermo Fisher Scientific cure this deficiency.
Thermo Fisher teach cell culture dishes are shallow containers to support the growth and propagation of cells in culture. They are available in a variety of sizes and formats with or without surface modification. Thermo Fisher Scientific teaches that different size dishes to include multi-well plates and dishes.
It would have been obvious to a person of ordinary skill in the art to use a multi-well plate of culture dish to support the neurons and pain mediators. Culture dishes and multi-well plates are the standard cell culture and commonly used in the art for cell culture models. There is a reasonable expectation of success given that methods of culture are well known and routine in the art.
The rejection of claims 15, 18, 20, 23,25, 28-30, 85 and 89 under 35 U.S.C. 103 as being unpatentable over Johnson et al. (“In vitro models for the study of osteoarthritis” The Veterinary Journal 209(2016) 40-49) and Wang et al. (“Animal and cellular models of chronic pain” Advanced drug delivery reviews vol. 55, Issue 8 Aug 2003, pp 949-965) in view of Kralj et al. (Optical recording of action potential in mammalian neurons using a microbial rhodopsin; Nat Method, 2011 9(1):90-95) is maintained.
The teachings of Johnson et al. and Wang et al. are presented in detail above. The references do not teach the neurons microbial rhodopsin protein. However, the teachings of Kralj et al. cure this deficiency.
Kralj et al. teach reliable optical detection of single action potentials are a long standing problem in neuroscience however, microbial rhodopsin expressed in culture neurons was able achieve this goal (Abstract). Kralj et al. teach the microbial rhodopsin was able to resolve individual action potential in mammalian neurons in vitro with high signal to noise ratio and low photoxicity (last para. of Introduction).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to express the microbial rhodopsin in the neurons of Wang et al. in the culture model made obvious by Johnson et al. and Wang et al. in order to view the action potentials of the neurons exposed to pain mediators. A person of ordinary skill in the art would have a motivation to detect the pain response in the neuron exposed to the pain mediators. There is a reasonable expectation of success given that Kralj et al. teach detection of single action potentials in neuronal cultures.
Response to Arguments
Applicant's arguments filed 8/6/25 have been fully considered but they are not persuasive. Applicants argue that the combination of references do not teach the composition. Applicants argue that the Johnson reports applying various mediators to cells or tissues to study pain but does not teach or suggest a composition that includes living neuron. Wang reports cultures of sensory neurons for studying pain but does not combine them with the mediator soup of claim 15 and does not teach the concentration of TNF. Applicants argue that Johnson reports TNF-alpha concentrations up to 50 ng/ml which represents opposite technical direction that would not suggest the claimed minimal threshold approach. Applicants argue that the claimed concentration and the prior art concentration do not overlap. Applicants argue that a skilled artisan would not swap one approach for another as they represent fundamentally different methodological boundaries. Applicants argue that by referring to up to 50 ng/ml, Johanson establishes this upper limit for their experimental work. Applicants argue that a person of ordinary skill in the art would stay within Johnsons established limits rather than venture into untested higher concentrations. Applicants argue the concentration is not a mere routine optimization. Applicants argue that the successful creation of this robust screening platform is an unexpected result. Applicants argue that the unexpected results is evidenced by consistent reproducible pain phenotypes generated across hundreds of cells (see Fig. 9 and 13). Applicants argue that Fig. 25 discloses unexpected technical advantages not taught by Johnson. Fig. 25 discloses that TNF-alpha at 50 and 100 ng/ml produces a dose dependent increase in current amplitude establishing a dose dependent relationship that extends beyond Johnsons maximum limit. Applicants argue that Johnson could not predict the synergistic effects achieved by the claimed multi-mediator composition at the specified threshold. Applicants argue that the secondary references to not cure these deficiencies.
These arguments were considered but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to create a model of OA pain using a plurality of pain mediators as taught by Johnson et al. and include neurons as taught by Wang et al. A person of ordinary skill in the art would have a motivation to include a living neuron because Wang et al. teach that the cultures have been found to be valuable for studying pain neurotransmitter release, elucidating signal transduction and identifying pain mediators. Furthermore, it would obvious to include neurons in the culture because Johnson et al. teach the cross talk between different tissues in OA joints dictate that models should consider the role of multiple tissues when assessing the response to a given stimulus, to enable more meaningful translation to the anticipated response in vivo As indicated above, the concentration of TNF is a result driven variable. In the instant case, Johnson et al. teach the concentration used in models are typically much higher at up to 100 ng/ml of IL-1beta and up to 50 ng/ml of TNF-alpha (p. 43, 1st col., 3rd para.). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the concentration of the plurality of pain mediators to arrive at the concentration that elicits a response in the model. Furthermore, the claimed concentration of TNF encompasses values that are numerically close to the disclosed range Optimization of such a result-driven variable would have been within the level of ordinary skill in the art. MPEP 2144.05 states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” In the instant case, the claimed concentration encompasses concentrations that are only incrementally higher than the upper limit of the prior art. Technically, greater than 50 ng/ml includes 50.1 ng/ml. Therefore, the concentrations encompassed by the claims are only marginally higher than the prior art and not the “opposite technical direction”. Routine experimental optimization in the art involved upward and downward adjustments around disclosed ranges to assess dose responses. There is no reason a person of ordinary skill in the art would avoid a slightly higher concentration. Importantly, the only distinction over the prior art is a minimal numerical increase over a disclosed upper limit and no unexpected results are tied to that increase. The arguments that there are unexpected results are not persuasive as the plurality of pain mediators are well known in the art and disclosed in Johnson. Furthermore, MPEP 716.02(a) states: “A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism”). No such evidence was shown. Furthermore, MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In the instant case, the claims are drawn to any interleukin, any growth factor, any protease and any TNF. The data presented is specific agents at specific concentrations. Furthermore, only one example of TNF-alpha was presented (100 ng/ml) and a single example is not commensurate is scope with the claims (the example of 50 ng/ml does not meet the limitation of “greater” than 50 ng/ml).
Importantly, the MPEP addresses ranges that are approaching the claimed limit. As presented above, MPEP 2144.05 states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” For the reasons presented above, the rejection is maintained.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654