Palo Alto Investors

Patent Trials and Appeals Board

Jan 27, 2022

2021001467 (P.T.A.B. Jan. 27, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/303,492 06/12/2014 Anthony Joonkyoo Yun PALO-029 6191 93726 7590 01/27/2022 EPA - BOZICEVIC FIELD & FRANCIS LLP BOZICEVIC, FIELD & FRANCIS 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER BORGEEST, CHRISTINA M ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 01/27/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte ANTHONY JOONKYOO YUN ____________ Appeal 2021-001467 Application 14/303,492 Technology Center 1600 ____________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and TAWEN CHANG, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method of improving a sympathetic bias associated autonomic nervous system associated condition in a subject. The Examiner rejected the claims as failing to comply with the enablement and written description requirements. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Palo Alto Investors (see Appeal Br. 3). We have considered the Specification of June 12, 2014 (“Spec.”); Final Office Action of Feb. 21, 2020 (“Final Act.”); Appeal Brief of July 17, 2020 (“Appeal Br.”); Examiner’s Answer of Oct. 23, 2020 (“Ans.”); and Reply Brief of Dec. 22, 2020 (“Reply Br.”). Appeal 2021-001467 Application 14/303,492 2 Statement of the Case Background “The hypothalamus is a portion of the brain that is located below the thalamus and above the brain stem that functions to maintain homeostasis in a subject” (Spec. 6:10-12). “[T]he hypothalamus functions to maintain homeostasis” of factors including “blood pressure, body temperature, fluid and electrolyte balance and body weight” based on “information from vagus, spinal cord, retina, and limbic and olfactory systems” by sending “neural signals to the autonomic system or endocrine signals to the pituitary” (Spec. 6:13-21). The Examiner explains that the term “autonomic nervous system” is sometimes used “to refer[] to both the parasympathetic and sympathetic nervous systems” (see Ans. 5). The Examiner explains that the sympathetic nervous system is “the part of the autonomic nervous system that contains chiefly adrenergic fibers and tends to depress secretion, decrease the tone and contractility of smooth muscle, and increase heart rate” (Ans. 5). The Specification addresses approaches for “at least partially restoring normal function of a central nervous system endocrine gland in a manner sufficient to improve the condition in the subject” (Spec. 2:10-12). According to the Specification, “[i]n some instances, the autonomic nervous system associated condition is a sympathetic bias associated condition” (Spec. 3:11-12). Appeal 2021-001467 Application 14/303,492 3 The Claims Claims 1, 2, 4, 12, 13, 29-31, and 33-39 are on appeal. Independent claim 1 is representative and reads as follows: 1. A method of improving a sympathetic bias associated autonomic nervous system associated condition in a subject, the method comprising: electrically stimulating the hypothalamus with electrodes placed in contact with the anterolateral hypothalamic region, the posteromedial hypothalamic region, or both, to increase activity in the anterolateral hypothalamic region and/or inhibit activity in the posteromedial hypothalamic region to at least partially restore normal function of the hypothalamus in a manner sufficient to modulate autonomic function to equalize the sympathetic/parasympathetic activity ratio to improve the condition in the subject, wherein the condition is a neurodegenerative condition. The Issues A. The Examiner rejected claims 1, 2, 4, 12, 13, 29-31, and 33-39 under 35 U.S.C. § 112, first paragraph as failing to comply with the enablement requirement (Ans. 9-19). B. The Examiner rejected claims 1, 2, 4, 12, 13, 29-31, and 33-39 under 35 U.S.C. § 112, first paragraph as failing to comply with the written description requirement (Ans. 19-24). A. 35 U.S.C. § 112, first paragraph, enablement The Examiner finds that: Due to the large quantity of experimentation necessary to adapt the teachings of the art in order to discover methods of carrying out the recited effects of modulating autonomic function . . . the lack of direction/guidance presented in the specification regarding the same and the absence of working Appeal 2021-001467 Application 14/303,492 4 examples directed to the same, the complex nature of the art and the invention, namely precise stimulation of a portion of the hypothalamus to achieve either increased parasympathetic or decreased sympathetic activity, and the breadth of the claims which fail to recite limitations on how to carry out the claimed methods in order to achieve the recited goals (i.e., parameters for hypothalamic electrical stimulation such as ideal intensity, frequency, pulse duration, electrode positioning, application time and nerve target), undue experimentation would be required of the skilled artisan to make and/or use the claimed invention. (Ans. 18-19). The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner’s conclusion that the claims fail to comply with the enablement requirement? Findings of Fact Breadth of Claims 1. Claim 1 is broadly drawn to “improving a sympathetic bias associated autonomic nervous system associated condition in a subject.” 2. The Specification teaches that: “Neurodegenerative conditions include neurodegenerative diseases, e.g., Alzheimer’s Disease, Pick’s Disease, Parkinson’s Disease, dementia, delirium, amyotrophic lateral sclerosis, and the like” (Spec. 33:17-20). This list is not exclusive and does not reasonably exclude neurodegenerative conditions such as Lewy Body disease, corticobasal degeneration, neuromylitis optica, Batten disease, and many other neurodegenerative diseases. Presence of Working Examples 3. There are no working examples for any of the specific diseases listed (see Spec. generally). Appeal 2021-001467 Application 14/303,492 5 Amount of Direction or Guidance Presented 4. The Specification provides generic teaching that “electrically modulating at least a portion of a subject’s autonomic nervous system’ is meant [as] altering or changing at least a portion of an autonomic nervous system by electrical means to provide a change, alteration or shift in at least one component or aspect of the function of the central nervous system endocrine gland. (Spec. 25:14-18). 5. The Specification does not, however, provide any details whatsoever regarding specific electrical stimulation protocols including voltage, amperage or electrical frequency. The Specification also does not provide details on the time frame for electrical stimulation or how often the therapy should be administered (see Spec. generally). 6. The Specification lists prior art devices “for applying electrical energy to a subject and which may be adapted for use in the subject invention are described, e.g., in U.S. Pat. Nos.: 7,149,574; 7,711,430; and 7,363,076; as well as U.S. Patent Application Serial No. 11/592,027; the disclosures of which are herein incorporated by reference” (Spec. 26:1-5). 7. The Specification2 was amended with text from US 7,149,574 at 9:41-59 to incorporate the following: Activation of the electrical energy supplying device directly applies the electrical output of the device, i.e., electrical energy, to the targeted area. For example, electrodes may be positioned to direct electrical impulses to specific nerve fibers, etc. The exact parameters of the protocol may vary depending on the particular subject, condition being treated, etc. An electronic current wave may be provided when the electrical 2 See Amendment to Specification filed with Request for Continued Examination on July 10, 2019. Appeal 2021-001467 Application 14/303,492 6 energy is applied. In certain embodiments, the current wave includes current waves of high frequency, e.g., high frequency pulses, where the current wave may also include low frequency amplitude modulation. In certain embodiments, a plurality of high frequency bursts of current pulses may be applied in addition to the application of underlying low frequency continuous stimulus. Monopolar or multipolar technologies may be employed. For example, to increase activity in a portion of the autonomic nervous system, voltage or intensity may range from about 1 millivolt to about 1 volt or more, e.g., 0.1 volt to about 50 volts, e.g., from about 0.2 volt to about 20 volts and the frequency may range from about 1 Hz to about 2500 Hz, e.g., about 1 Hz to about 1000 Hz, e.g., from about 2 Hz to about 100 Hz in certain embodiments. In certain embodiments pure d- c voltages may be employed. The pulse width may range from about 1 microsecond to about 2000 microseconds or more, e.g., from about 10 microseconds to about 2000 microseconds, e.g., from about 15 microseconds to about 1000 microseconds, e.g., from about 25 microseconds to about 1000 microseconds. The electrical output may be applied for at least about 1 millisecond or more, e.g., about 1 second, e.g., about several seconds, where in certain embodiments the stimulation may be applied for as long as about 1 minute or more, e.g., about several minutes or more, e.g., about 30 minutes or more may be used in certain embodiments. (Spec. 26:6). 8. The Examiner finds, regarding this incorporation by reference, that the “skilled artisan is tasked with discovering the voltage, frequency, pulse width and duration of electrical stimulation to be applied to the hypothalamus in order to achieve equalizing the sympathetic/ parasympathetic activity ratio so as to achieve the recited effects in the claims” (Ans. 12). Appeal 2021-001467 Application 14/303,492 7 9. Appellant previously argued that the disclosure in FF7 “does not describe restoring normal endocrine function using electrical stimulation of central nervous system endocrine glands and is in fact silent to electrical stimulation of central nervous system endocrine glands . . .Yun is silent to electrical stimulation of central nervous system endocrine glands, let alone doing so to restore endocrine function” (Appellant’s Response filed Jan. 15, 2016, referencing Yun, US 2004/0249416 that is the PGPub of US 7,149,574 and therefore shares the identical Specification). State of the Prior Art and Unpredictability of the Art 10. Sironi3 teaches, as of 2011, regarding electrical stimulation of the brain that “there are still many unresolved technical and ethical problems, concerning the identification of the targets for each disease, the selection of the patients and the evaluation of the results” (Sironi 1, abstract). 11. Sironi teaches that stimulation with different electrical frequencies yield different results, teaching that “that, while ‘low-frequency stimulation’ (5-10 Hz) could enhance tremor and other correlated symptoms, ‘high-frequency stimulation’ (50-100 Hz) resulted in a reduction of symptoms” (Sironi 2, col. 2). 12. Sironi teaches: The potentials of this neurotechnique are fascinating, but many questions still remain unanswered. Several technical and ethical problems have to be still solved. What are the optimal targets for each disease? What other neurological and psychic disorders can [deep brain stimulation (DBS)] be applied to? What should be the criteria for selecting candidates? Only when they are or 3 Sironi, Origin and evolution of deep brain stimulation, 5 Frontiers in Integrative Neuroscience 1-5 (2011). Appeal 2021-001467 Application 14/303,492 8 are considered as? For some diseases should DBS be used regardless of pharmacological therapy? Could an early use of DBS change the natural history of some kinds of disease? In addition, an objective and statistically valid assessment of long- term results and of possible technique-related complications is still central. (Sironi 4, col. 1). 13. Gubellini4 teaches “[s]ize, shape and area of the microelectrode can affect the spatial distribution of the current density on the electrode surface and the electric field generated within the brain tissue, and overall affect brain tissue reactivity and potential neural damage” (Gubellini 86, col. 2). The Specification provides no guidance regarding electrode size or design (see FF 7). 14. Gubellini teaches “electrode material and its possible degradation, charge density (that depends on electrode surface), and duration and waveform of stimuli can have a significant impact not only on the effect and the efficacy of DBS, but also on the safety of this method” (Gubellini 88, col. 2). The amendments to the Specification provide very limited guidance on charge density, waveform, or duration of stimulation (see FF 7). 15. Krack5 teaches, regarding DBS in the brain, that the “functional outcome of these complex putative mechanisms of action is uncertain and is probably variable, depending on the specific anatomophysiological arrangements of each target region” (Krack 477, col. 1). 4 Gubellini et al., Deep brain stimulation in neurological diseases and experimental models: From molecule to complex behavior, 89 Progress in Neurology 79123 (2009). 5 Krack et al., Deep brain stimulation: from neurology to psychiatry?, 33 Trends in Neuroscience 474-84 (2010). Appeal 2021-001467 Application 14/303,492 9 16. Leone6 teaches “that acute hypothalamic stimulation is ineffective as a treatment for CH [cluster headache]” while “several weeks of continuous stimulation are required before the attacks are markedly reduced or eliminated” (Leone 189, col. 1-2). 17. Leone teaches the “latency of chronic stimulation and inefficacy of acute stimulation suggest that the mechanism of hypothalamic stimulation is complex and not the result of simple inhibition of hypothalamic neurons” (Leone 193, col. 1). 18. Lim7 teaches: Electrical stimulation of the [dorsolateral periaqueductal gray] and [ventromedial hypothalamus] produced a typical behaviour consisting of vigorous running and jumping in rat, referred as escape behaviour. This behaviour in rodents has been considered a phenomenon closely mimicking [panic attack] in humans. Our results have revealed that the most important stimulation parameter for this behaviour is the stimulation amplitude. (Lim 200, col. 2). 19. Lim teaches that even “with 300 Hz stimulation with a threshold-amplitude, rats showed escape behaviour. These findings suggest that both [dorsolateral periaqueductal gray] and [ventromedial hypothalamus] are not sensitive for high-frequency stimulation in the context of escape behaviour. This is in contrast with findings in animal models of Parkinson’s disease [and other diseases]” (Lim 200, col. 2). 6 Leone et al., Hypothalamic deep brain stimulation in the treatment of chronic cluster headache, 3 Therapeutic Advances in Neurological Disorders 187-95 (2010). 7 Lim et al., High-frequency stimulation of the dorsolateral periaqueductal gray and ventromedial hypothalamus fails to inhibit panic-like behavior, 193 Behavioural Brain Res. 197-203 (2008). Appeal 2021-001467 Application 14/303,492 10 20. Cortelli teaches the intensity of stimulation, determined by its efficacy in relieving [cluster headache], could have been below the threshold for an autonomic effect. However, this hypothesis is unlikely because the acute monopolar and bipolar stimulation of [posterior hypothalamic area] for 20 min with the same frequency and pulse width used in our study but with a higher amplitude of 4-5 V caused general malaise, generalized sweating, dizziness and diplopia but did not change [blood pressure] or [heart rate]. (Cortelli 6, col. 1). 21. Cortelli teaches “that after [deep brain stimulation] of the [posterior hypothalamic area] our subjects did not refer any changes to the sleep-wake cycle or their behaviour may suggest a different targeting of the stimulating electrodes in our patients, possibly more caudal” (Cortelli 7, col. 1; citation omitted). 22. Fasano8 teaches “despite widespread use of DBS, the mechanisms through which it alleviates the symptoms of Parkinson’s disease are not fully understood; further research is needed on this important topic. Moreover, the present data show that the amount of improvement after DBS implants depends on relevant individual variations” (Fasano 438, col. 1). 23. Fasano teaches, for Parkinson’s patients, “an improvement of gait with stimulation at low frequencies (10-25 Hz) and a worsening at higher frequencies (>80 Hz)” (Fasano 431, col. 2). Fasano also teaches “there is a cogent need to associate the precise electrode location with surgical outcome as well as to search for predictive factors of long-term outcome after DBS” (Fasano 438, col. 1). 8 Fasano et al., Treatment of motor and non-motor features of Parkinson’s disease with deep brain stimulation, 11 Lancet Neurol. 429-42 (2012). Appeal 2021-001467 Application 14/303,492 11 24. Aldehri,9 a postfiling date reference, teaches: “It is still premature to conclude that DBS can be used in the treatment of AD, and the field will wait for the results of ongoing and future clinical trials” (Aldehri abstract). Aldehri teaches studies of DBS in Table 1, reproduced below: 9 Aldehri et al., Deep brain stimulation for Alzheimer’s Disease: An update, 9 Surgical Neurol. International, 58 (2018). Appeal 2021-001467 Application 14/303,492 12 (Aldehri, Table 1). Quantity of Experimentation 25. Krack teaches that “efficacy can be tested in randomized, double-blind, controlled clinical trials” (Krack 474, col. 2), which require significant investment of resources and effort. 26. The Examiner finds that a “large quantity of experimentation [would have been] necessary to adapt the teachings of the [prior] art in order to [be capable] of carrying out the recited effects of modulating autonomic function so that the sympathetic/parasympathetic bias of the subject is closer to that of a healthy 25 year old” (Ans. 18). Skill in the Art 27. The cited art, replete with papers from medical doctors, suggests that the skill in the art is high (cf. FF 8-21). Appeal 2021-001467 Application 14/303,492 13 Principles of Law Factors to be considered in determining whether a disclosure would require undue experimentation . . . include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Analysis “The requirement of enablement, stated in 35 U.S.C. § 112, enforces the essential ‘quid pro quo of the patent bargain’ by requiring a patentee to teach the public how ‘to practice the full scope of the claimed invention.’” Pacific Biosciences California, Inc. v. Oxford Nanopore Tech., Inc., 996 F.3d 1342, 1350 (Fed. Cir. 2021) (citing McRO, Inc. v. Bandai Namco Games America Inc., 959 F.3d 1091, 1096 (Fed. Cir. 2020). “[A] patentee chooses broad claim language at the peril of losing any claim that cannot be enabled across its full scope of coverage.” MagSil Corp. v. Hitachi Glob. Storage Techs., Inc., 687 F.3d 1377, 1381 (Fed. Cir. 2012) We agree with the Examiner that these claims require undue experimentation for the public to practice and do not provide a disclosure that satisfies the quid pro quo of the patent bargain. Claim 1 is a method broadly encompassing the treatment of any degenerative disease, whether disclosed by the Specification or not (FF 1-2). The Specification not only lacks any working examples (FF 3), but also provides no detailed guidance regarding the electric characteristics of any stimulation as it relates to specific diseases, the precise location of Appeal 2021-001467 Application 14/303,492 14 stimulation, the size and location of electrodes, or the frequency of stimulation therapy (FF 4-9). While the Specification was amended to provide very broad and non-detailed generalities regarding frequency, intensity, pulse times and pulse lengths (FF 7), the Specification does not provide guidance on how this generalized information relates to neurodegenerative diseases. Indeed, “the specification omitted crucial details (e.g. . . . process conditions) for teaching even a single way of producing the claimed result for the identified matter.” McRo, 959 F.3d at 1101. As to unpredictability, the cited prior art is replete with statements like those of Krack that treatment with electrical stimulation of various diseases is “uncertain and is probably variable, depending on the specific anatomophysiological arrangements of each target region” (FF 15). Sironi evidences that different stimulation parameters give different results (FF 10- 12), while Gubellini explains that the shape of the electrode also affects the treatment (FF 13), as does the waveform of the stimuli itself (FF 14). Leone also shows that hypothalamic stimulation is ineffective as an acute treatment for chronic headache (FF 16) and that, even if it is effective in long-term treatment, the “mechanism of hypothalamic stimulation is complex” (FF 17). Lim shows that stimulation parameters that work for one disease do not necessarily apply to other diseases like neurodegenerative diseases (FF 18- 19). Cortelli also demonstrates that electrode placement in the brain is unpredictable, where “after [deep brain stimulation] of the [posterior hypothalamic area] our subjects did not refer any changes” and this “may suggest a different targeting of the stimulating electrodes in our patients, Appeal 2021-001467 Application 14/303,492 15 possibly more caudal” (FF 21). Similarly, Fasano teaches “there is a cogent need to associate the precise electrode location with surgical outcome as well as to search for predictive factors of long-term outcome after DBS” (FF 23). The Specification provides no specific guidance on precise locations for electrodes within the brain for treatment of any neurodegenerative condition. Aldehri evidences that clinical trials would be required to determine if deep brain stimulation functions on any particular disease (FF 24). Therefore, as to the quantity of experimentation, the evidence supports the Examiner’s finding that a significant quantity of experimentation would have been required (FF 26). Krack teaches that “efficacy can be tested in randomized, double-blind, controlled clinical trials” (FF 25), which require significant investment of resources and effort. A preponderance of the evidence therefore supports the Examiner’s repeated finding that the invention requires undue experimentation because the skilled artisan is tasked with discovering the voltage, frequency, pulse width and duration of electrical stimulation to be applied to the hypothalamus in order to achieve equalizing the sympathetic/parasympathetic activity ratio so as to treat neurodegenerative disease; to restore endocrine function to that of a healthy human 25 year old; to modulate autonomic function so that the sympathetic/parasympathetic bias is closer to that of a healthy human 25 year old; to at least partially restore the normal function of the hypothalamus and to improve diabetes and hypertension. In light of the disclosure of such broad parameters, the claims are an invitation to further experimentation in order to discover the ideal parameters for equalizing the sympathetic/parasympathetic activity ratio. (Ans. 53). Appeal 2021-001467 Application 14/303,492 16 The Examiner has set forth a reasonable basis for finding that the scope of the appealed claims is not enabled by the general description and the single working example in the specification. Consequently, the burden shifted to [Appellants] to present persuasive arguments, supported by suitable proofs where necessary, that the appealed claims are truly enabled. In re Wright, 999 F.2d 1557, 1562 (Fed. Cir. 1993). Here, where there is not even a single working example or description of a detailed treatment procedure, as well as significant evidence of unpredictability and large amounts of experimentation, Appellant fails to meet this burden. Appellant contends “that the specification clearly lists specific parameters for achieving autonomic nervous system modulation by electrical stimulation. Indeed, the specification clearly lists such as ideal intensity (e.g., 1 millivolt to . . . about 50 volts[)] . . . frequency (1 Hz to about 2500 Hz) . . . and pulse duration (1 millisecond or more, e.g. . . . about 30 minutes or more)” (Appeal Br. 6-7). We do not agree that these are “specific parameters” for disease treatment. For example, Fasano teaches in Parkinson’s patients “an improvement of gait with stimulation at low frequencies (10-25 Hz) and a worsening at higher frequencies (>80 Hz)” (FF 23). Thus, two frequency ranges both falling within the range disclosed by Appellant have two entirely different effects on patients. Appellant’s ranges for pulse intensity, pulse frequency, and pulse duration do not provide sufficient information for treatment of any specific disease but rather constitute general guidance that would require further undue experimentation to apply to any particular patient with a particular disease condition. “Although a specification does not need to ‘describe how to make and use every possible variant of the Appeal 2021-001467 Application 14/303,492 17 claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.’” Amgen, Inc. v. Sanofi, 987 F3d.1080, 1085 (Fed. Cir. 2021) (citing McRo, 959 F.3d at 1100). “The patent itself acknowledges a need for further experimentation to determine the necessary or optimal value of certain variables.” In re Hoffman, 558 Fed. Appx. 985, 987 (Fed. Cir. 2014). Appellant contends that “the Examiner has mischaracterized the . . . statements regarding Yun” (Appeal Br. 8). Appellant contends there is no inconsistency between their incorporation by reference of Yun’s teachings and their arguments over Yun as prior art because Yun does not teach electrical stimulation applied to the same portion of the autonomic nervous system as the instantly claimed method. While Yun discloses the genus of autonomic nervous system modulation, the reference does not disclose the species of electrically stimulating a central nervous system endocrine gland such as the hypothalamus. (Id.). Even if we agree with Appellant that there was no inconsistency (and we agree with the Examiner), Appellant’s own argument here demonstrates the lack of enablement concern. Appellant points out that the precise location of electrical stimulation matters, but does not persuasively explain where the Specification teaches, for any particular neurological disease, where that stimulation should occur. We also find unpersuasive Appellant’s argument that “skilled artisan would readily understand how to apply the electrical modulation in order to improve the sympathetic bias mediated condition as claimed” by stimulating various hypothalamic regions (see Appeal Br. 9-10). We appreciate that Appellant provides general disclosure connecting hypothalamic portions Appeal 2021-001467 Application 14/303,492 18 with a long list of conditions (see Spec. 10, 33), but Appellant has provided insufficient information regarding electrical stimulation parameters for a single neurological disease such as Alzheimer’s disease, much less any neurodegenerative condition whatsoever. Indeed, even post-filing date art such as Aldehri suggests that more evidence is required in 2018 to show the efficacy of DBS in Alzheimer’s disease (FF 24). Aldehri specifically discusses at least eleven different studies which list specific stimulation parameters such as a Fornix study in humans with bilateral stimulation at 3.0 V, 130 Hz, and 90 microsecond pulse width for 12 months and an anteromedial thalamic nucleus study in rats with unilateral stimulation at 100 Hz, 60 microsecond pulse width for 30 minutes (FF 24). And yet, Aldehri concludes that even five years post filing date, in 2018, “[deep brain stimulation] does not prevent neurodegeneration in [Alzheimer’s disease]”; that “[m]ore research needs to be done to establish the criteria needed for the treatment approach in patients with [Alzheimer’s disease]”; and that “there are multiple groups focusing on different targets in the brain, which makes drawing solid conclusions rather difficult” (Aldehri at 7). Appellant contends “Cortelli provides evidence that electrically stimulating the hypothalamus as claimed does, indeed, modulate the autonomic nervous system” (Appeal Br. 12). We find this argument unpersuasive. While Cortelli does teach that electrode placement, voltage pulse width, and frequency were optimized (see Cortelli 2, col. 1), Cortelli also recognized that a different targeting may be needed (FF 21) and that “stimulation of the PHA is not effective as an acute treatment of CH attacks but chronic stimulation of the same brain area is Appeal 2021-001467 Application 14/303,492 19 effective” (Cortelli 7, col. 1). Thus, Cortelli’s disclosure is limited to the very particular disease condition and parameters tested, and does not provide enabling support for the much broader class of neurodegenerative diseases, other electrode placements, or other electrical and timing conditions needed to treat these neurodegenerative diseases. We disagree with Appellant’s argument that “even if Gubellini teaches that high frequency stimulation affects parts of the brain differently, this does not somehow inject and [sic] undue amount of unpredictability into the claimed method such that it is non-enabled” (Appeal Br. 12). That detailed and difficult experimentation for each particular disease, amounting to a clinical trial for human patients, using different optimized electrical parameters, electrode types and locations, is the essence of undue experimentation. As we stated earlier, the quid pro quo for the patent system is not providing a general suggestion inviting others to experiment with unpredictable and complicated systems until they find a solution, but rather delivering enough detailed guidance of a completed solution that, at most, limited experimentation is required. In re Ghiron, 442 F.2d 985, 992 (CCPA 1971) (a development period of “many months or years . . . does not bespeak a routine operation but of extensive experimentation and development work.”) We also are not persuaded by Appellant’s reliance on Hilton10 (see Appeal Br. 12-13), a 1971 paper that provides no guidance on parameters necessary to treat any neurodegenerative disease. It is those disease specific parameters, not general parameters that cause other biological effects, that 10 Hilton and Spyer, Participation of the anterior hypothalamus in the baroreceptor reflex, 218 J. Physiol. 271-293 (1971). Appeal 2021-001467 Application 14/303,492 20 must be disclosed to enable the present claims. No such specific parameters are reasonably found, even in incorporated by reference portion of the Specification. Instead, general discussion of parameters is all that is presented in the Specification (FF 7). And while we agree with Appellant that the age of the Hilton reference does not necessarily detract from its value in assessing enablement (see Reply Br. 10), the absence of any specific disclosures regarding elements of the claims significantly limits any persuasive argument based on Hilton. Claims 2 and 4 Claims 2 and 4 further limit claim 1 to “restoring endocrine function” or “sympathetic/parasympathetic bias” to a function that “is closer to that of a healthy human 25 year old.” Appellant contends the Specification enables an artisan “to modulate the endocrine gland (i.e., hypothalamus) with guidance from the instant specification (as discussed above), and adjust the parameters of the modulation so that the subject’s endocrine function and parasympathetic/sympathetic function fall in line with what would be expected from a healthy 25 year old” (Appeal Br. 17). The Examiner finds It would be an extraordinary achievement to be able to modulate the autonomic system of an aged individual suffering from a neurodegenerative disease, diabetes and/or hypertension by applying electrical stimulation to . . . restore endocrine function to that of a healthy 25 year old. Aging is an inevitable and ultimately terminal process. (Ans. 59-60). The Examiner finds the “enablement issue was raised because the disclosure does not provide sufficient guidance . . . as to the parameters for electrical stimulation that can achieve the extraordinary result” (id. at 60). Appeal 2021-001467 Application 14/303,492 21 We agree with the Examiner. While Carl Sagan may have felt that extraordinary claims require extraordinary evidence, patent law does not. But when the Examiner establishes a prima facie case of lack of enablement, as here, Appellant cannot simply provide a general assertion that the claims are enabled. The burden is shifted to Appellant “to present persuasive arguments, supported by suitable proofs where necessary, that the appealed claims are truly enabled.” Wright, 999 F.2d at 1562. No persuasive or particular evidence, disclosure of electrical stimulation conditions, experiments, prior art, or working examples are provided that teach how to return a patient’s biological functions to those of a healthy 25 year old. Appellant does not satisfy their burden to demonstrate that these claims are enabled. Claims 12 and 13 Claims 12 and 13 are drawn to decreasing degeneration of the hypothalamus or of non-endocrine gland cells. Appellant contends a skilled artisan would “understand that hypothalamic dysfunction is implicated in neurodegenerative conditions, and therefore that the claimed method of electrically modulating the hypothalamus and thereby increasing its functioning can improve the prognosis of neurodegenerative conditions such as Alzheimer’s disease” (Appeal Br. 18). Appellant cites Loskutova11 as teaching several studies demonstrate evidence of increased sympathetic activity including increased brain noradrenergic activity and elevated serum and cerebrospinal fluid levels of norepinephrine. Why increased activity has been observed in some aspects of 11 Loskutova et al., Reduced Limbic and Hypothalamic Volumes Correlate with Bone Density in Early Alzheimer’s Disease, 20 J. Alzheimers Dis. 313- 22 (2010). Appeal 2021-001467 Application 14/303,492 22 the hypothalamic-pituitary axis in AD remains unclear but may be related to disturbed negative feedback while increased SNS activity may be related to overcompensation of remaining noradrenergic neurons in response to profound noradrenergic neuronal loss. (Appeal Br. 19, citing Loskutova 6; emphasis omitted). We find this reasoning insufficient for the reasons already given. Even if there is a relationship between increased activity in the hypothalamus and Alzheimer’s disease, a relationship that is not clearly proven, Appellant fails to provide detailed guidance, working examples, or predictable electrical treatment parameters that would enable the ordinary artisan to treat a patient to decrease degeneration of the hypothalamus or gland cells. Appellant does not satisfy their burden to demonstrate that these claims are enabled. Claims 36-39 Claims 36 and 37 are drawn to diabetes as the disease condition and claims 38 and 39 are drawn to cardiovascular conditions, particularly hypertension. Appellant contends claims 36 and 37 are “enabled because diabetic pathophysiology is related to autonomic nervous system functioning, and can therefore be addressed by modulating the parasympathetic/sympathetic nervous system ratio” and that claims 38 and 39 “are enabled because it is well known that the cardiovascular system is sensitive to changes in the parasympathetic/sympathetic activity ratio” (Appeal Br. 20). We find this reasoning insufficient for the reasons already given above. Even if we concede that there is a known relationship, that is not sufficient to enable treatment of either diabetes or cardiovascular conditions generally. Appellant fails to provide detailed guidance, working examples, Appeal 2021-001467 Application 14/303,492 23 or predictable electrical treatment parameters that would enable the ordinary artisan to treat a patient to treat diabetes or cardiovascular conditions generally using electrical stimulation of the hypothalamus. Appellant does not satisfy their burden to demonstrate that these claims are enabled. Conclusions of Law As we balance the Wands factors, we find the balance of factors, including a large quantity of experimentation, the minimal guidance in the Specification, the absence of any working examples, the lack of any nexus for the breadth of neurodegenerative disease treatments and the electrical stimulation treatment, the unpredictability of the art regarding electrical stimulation with the limited set of diseases tested, and the large breadth of the claims, weighed against a high skill level in the art, support the Examiner’s conclusion that undue experimentation would have been required to enable the full scope of the instantly claimed invention. The evidence of record supports the Examiner’s conclusion that the claims fail to comply with the enablement requirement. B. 35 U.S.C. § 112, first paragraph, written description The Examiner finds “the skilled artisan cannot envision the detailed steps necessary to achieve the recited goals, namely, the ideal intensity, frequency, pulse duration, electrode positioning, application time and nerve target, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of optimization” (Ans. 23-24). “Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method” (id. at 24). Appeal 2021-001467 Application 14/303,492 24 Appellant contends the Examiner “has the initial burden of presenting by a preponderance of evidence why a person skilled in the art would not recognize in an applicant’s disclosure a description of the invention defined by the claims” (Appeal Br. 21). Appellant contends “the instant specification sufficiently describes equalizing the sympathetic/parasympathetic activity ratio through stimulation of CNS endocrine glands” (id.). Appellant contends “the specification clearly describes the use of electrical stimulation to perform the claimed modulating of autonomic function to equalize the sympathetic/parasympathetic activity ratio” (id. at 22). And Appellant contends that the matter incorporated by reference from Yun “teaches that such electrical stimulation may be performed by placing an electrostimulatory device directly on or about the targeted area and how such stimulation may be carried out, including exemplary electrical impulses that may be delivered and the timing of such” (id. at 23). We agree with the Examiner. “[I]t is the specification itself that must demonstrate possession. And while the description requirement does not demand any particular form of disclosure, . . . or that the specification recite the claimed invention in haec verba, a description that merely renders the invention obvious does not satisfy the requirement” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010). The instant Specification does not describe any specific steps, including details of specific electrical stimulation protocols that actually treat any neurodegenerative disease that would establish possession of the claimed invention. Even if the claims were limited to a single particular disease, which most are not, no electrical stimulation protocols are disclosed. Appeal 2021-001467 Application 14/303,492 25 These details matter. Just as an antibody is not described simply by disclosing an antigen (see Amgen v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017)), a functional method to “at least partially restore normal function” to improve a neurodegenerative condition as in claim 1 is “no more than a ‘wish or plan for obtaining the claimed [] invention’ and did ‘not provide any guidance that would steer the skilled practitioner toward compounds that can be used to carry out the claimed methods.’” Novozymes A/S v. Dupont Nutrition Biosci. APS, 723 F.3d 1336, 1347 (Fed. Cir. 2013). Without any link between the general concept of electrical stimulation of the hypothalamus and specific treatment parameters that result in some therapeutic effect on the list of neurodegenerative diseases encompassed by claim 1 (FF 1-2), diabetes in claim 36 or cardiovascular conditions in claim 38, it is not sufficient to state that prior art (or post-filing date art) treated other conditions using particular devices and parameters and, in a limited set of cases, obtained positive results. We continue to find this situation analogous to Fujikawa, where the court found an “application contained no blazemarks as to what compounds, other than those disclosed as preferred, might be of special interest. In the absence of such blazemarks, simply describing a large genus of compounds is not sufficient to satisfy the written description requirement as to particular species or sub-genuses.” Fujikawa v. Wattanasin, 93 F.3d 1559, 1571 (Fed. Cir. 1996). Similarly here, there are no blazemarks in the Specification to any particular electrical waveforms, frequencies, electrodes, or other parameters that yield therapeutic effects on the hypothalamus sufficient to treat these diseases. And while it might be obvious to optimize the Appeal 2021-001467 Application 14/303,492 26 conditions that were incorporated by reference to Yun, obviousness is not the standard for written description. Ariad, 598 F.3d at 1352. Appellant has not provided sufficient evidence to establish that they conceived and described sufficient representative species encompassing the breadth of the genus and therefore have “only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014). To the extent that Appellant relies upon the prior art to describe specific details of electrical devices, electrodes, waveforms and other elements that might be obvious to apply to the particular disease conditions encompassed by claims 1 and 36-39, Appellant does not establish that the prior art does, in fact, render these details obvious. Claims 2, 4, 12, 13, and 36-39 We find that the same logic applies to these claims. As discussed immediately above, Appellant provides an insufficient description of the details of the invention regarding electrical devices, electrodes, waveforms, and other elements specific to the particular disease conditions, just as in Amgen, insufficient details of the antibody were provided to establish the claim. We therefore conclude that Appellant has not satisfied the written description requirement for the pending claims. Appeal 2021-001467 Application 14/303,492 27 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2, 4, 12, 13, 29-31, 33-39 112(a) Enablement 1, 2, 4, 12, 13, 29-31, 33-39 1, 2, 4, 12, 13, 29-31, 33-39 112(a) Written Description 1, 2, 4, 12, 13, 29-31, 33-39 Overall Outcome 1, 2, 4, 12, 13, 29-31, 33-39 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED