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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 4, 2026 and amendment after final filed on February 4, 2026 has been entered. Claim 3 was canceled and claims 1, 4-19 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL in a previous office action.
Claims 2, 5-6, 14-19 are withdrawn from consideration as being drawn to non-elected invention/species.
Claims 1, 4, 7-13 are examined on the merits of this office action
Declaration under 37 C.F.R. 1.132
The Declaration under 37 CFR 1.132 filed February 4, 2026 is insufficient to overcome the rejection of claims 1, 7-12 in view of Dongsheng (WO2014179139 A2) in view of Happ (Fertility and Sterility, Volume 43, No. 4, 1985) as evidenced by CDC (see attached handout), Belchetz (AAAS, 1978, volume 202, 10) and Wilson (Arch. Gen. Psychiatry, 2007).
Applicants argue that GnRH neurons are developmentally and anatomically linked to the olfactory system and that olfactory dysfunction is associated with GnRH deficiency.
Applicant’s arguments have been fully considered but not found persuasive. The pending claims do not require any particular biological mechanism linking olfactory dysfunction and GnRH deficiency. The rejection does not rely upon an specific mechanism of action. Rather, Dongsheng teaches treating cognitive decline with GnRH, Happ and Belchetz teach administering GnRH in a physiological pulsatile manner, and Wilson teaches that olfactory dysfunction is associated with cognitive decline in older adults and predicts the development of mild cognitive impairment. Whether the therapeutic effect occurs through the mechanism proposed by Declarant does not negate the obviousness of the claimed method.
Applicant argues that cognitive impairment associated with olfactory dysfunction represents a distinct patient population.
Applicant’s arguments have been fully considered but not found persuasive. Wilson teaches that impaired odor identification is associated with lower global cognition, more rapid cognitive decline, and predicts the subsequent development of mild cognitive impairment in older adults. Thus, patients having both cognitive impairment and olfactory dysfunction were recognized in the prior art. Selecting this recognized subgroup from the broader elderly cognitive impaired population taught by Donsheng would have been an obvious matter of patient selection.
Applicant argues that pulsatile GnRH treatment alleviates cognitive impairment in patients exhibiting olfactory dysfunction.
Applicant’s arguments have been fully considered but not found persuasive. Dongsheng already teaches administering GnRH to improve cognitive decline, while Happ and Belchetz teach that pulsatile administration is the physiologically appropriate manner of administering GnRH. Therefore, the alleged therapeutic benefit does not demonstrate that the claimed method would have been unexpected, as the applied references collectively teach both the therapeutic agent and the claimed administration regimen.
Applicant argues that the inventors discovered a previously unrecognized relationship between olfactory dysfunction and cognitive impairment.
Applicant’s arguments have been fully considered but not found persuasive. Wilson expressly teaches that impaired odor identification predicts the development of mild cognitive impairment, is associated with lower global cognition and more rapid cognitive decline, and suggests that olfactory dysfunction is an early manifestation of Alzheimer’s disease, Accordingly, the relationship between olfactory dysfunction and cognitive impairment was recognized in the art prior to Applicant’s filing.
Applicant argues that the claimed invention addresses patients having both a cognitive disorder and olfactory dysfunction.
Applicant’s arguments have been fully considered but not found persuasive. Dongsheng teaches treating cognitive decline in elderly patients using GnRH. Wilson teaches that olfactory dysfunction is associated with cognitive decline in older adults and identifies patients exhibiting both conditions as a recognized patient population. Therefore, it would have been obvious to administer Dongsheng’s known GnRH treatment to patients having both a cognitive disorder and an olfactory dysfunction. The amendment merely identifies a known subgroup of patients and does not alter the obviousness of the claimed treatment in view of the combined teachings of Dongsheng, Wilson, Happ and Belchetz.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Withdrawn Rejections
The rejection of claim(s) 1, 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Dongsheng (WO2014179139 A2) in view of Happ (Fertility and Sterility, Volume 43, No. 4, 1985) as evidenced by CDC (see attached handout) and Belchetz (AAAS, 1978, volume 202, 10) is withdrawn in view of the amendment filed February 4, 2026.
The rejection of claim(s) 1, 7-13 under 35 U.S.C. 103 as being unpatentable over Dongsheng (WO2014179139 A2) in view of Happ (Fertility and Sterility, Volume 43, No. 4, 1985) as evidenced by CDC (see attached handout) and Belchetz (AAAS, 1978, volume 202, 10) as applied to claims 1, 7-12 above in further view of DrugBank (Gonadorelin, Uses, Interactions and Mechanism of action, published online 2005, cited previously) is withdrawn in view of the amendment filed February 4, 2026.
The rejection of claim 1, 4, 7-13 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 in view of the amendment filed February 4, 2026.
Maintained/Revised Rejection
Claim Rejections - 35 USC § 112, first paragraph
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, 4, 7-13 remain 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 treating patients with specific cognitive disorders does not reasonably provide enablement for treating or alleviating cognitive defects in patients having both a cognitive disorder and an olfactory dysfunction. Although the specification discusses olfactory dysfunction generally and describes testing olfactory dysfunction, it does not reasonably enable treatment of the full scope of patients encompassed by the claims who have both conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors 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, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of the claims
The claims are drawn to “A method for alleviating, reducing a cognitive defect in a mammalian patient having a cognitive disorder with an olfactory dysfunction, said method comprising a pulsatile administration of gonadotropin-releasing hormone (GnRH) to said mammalian patient, wherein said administration is made in a manner to reproduce natural endogenous GnRH pulsatile peaks observed in a control population of same gender as the mammalian patient.” Claim 4 is drawn to down syndrome, claim 7 claims the disorder is age associated cognitive decline and claim 8 now claims “wherein said cognitive disorder is in an asymptomatic preclinical stage or an intermediated stage corresponding to mild cognitive impairment”.
Furthermore, regarding “cognitive disorder”, Applicant’s specification states “ “Cognitive disorders”, also referred to as “neurocognitive disorders” are characterized by decline from a previously attained level of cognitive, i.e. a decline in perceptual-motor function (visual perception, visuoconstructional reasoning, perceptual-motor coordination), language (object naming, word finding, fluency, grammar and syntax, receptive language), learning and memory (free recall, cued recall, recognition memory, semantic and autobiographical long term memory, implicit learning), social cognition (recognition of emotions, theory of mind, insight), complex attention (sustained attention, divided attention, selective attention, processing speed) and executive function (planning, decision making, working memory, responding to feedback, inhibition, flexibility). For review, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V—a reference in the field) published by the American Psychiatric Association (APA), provides a common framework for the diagnosis of neurocognitive disorders. DSM-V particularly describes the main cognitive syndromes. It divides cognitive disorders into three categories: delirium, mild and major neurocognitive disorders, and defines criteria to delineate specific aetiological subtypes of mild and major neurocognitive disorders. The principal aetiological subtypes are Alzheimer disease; frontotemporal lobar degeneration, HIV infection, Huntington disease, Lewy body disease, Parkinson disease, Prion disease, Substance and/or medication use, traumatic brain injury and vascular disease” (see paragraph 0048). There are no specific definitions with regards to “cognitive defects” and thus will be interpreted as any kind of defect or change in cognition. Cognition is “relating to the process of acquiring knowledge and understanding through thought, experience, and the senses.”
Regarding the limitation requiring the patient to have an olfactory dysfunction, the specification defines olfactory dysfunction broadly as anosmia, hyposmia, or microsmia and provides examples of olfactory testing. However, the specification does not provide sufficient guidance demonstrating that pulsatile GnRH therapy is effective throughout the full scope of patients having both a cognitive disorder and an olfactory dysfunction. The claims encompass numerous cognitive disorders, numerous causes of olfactory dysfunction, varying disease stages, and numerous patient populations without corresponding representative working examples.
The State of the Prior Art
While GnRH therapy is well known in the field of reproductive endocrinology, its role in cognitive modulation is not well established or routine. There is little prior art teaching how to deliver pulsatile GnRH to affect cognition or olfactory performance, let alone to calibrate pulses to match species and gender specific physiological patterns.
Prevot (cited previously) teaches “Exogenous GnRH has been shown to cross the blood–brain barrier (23). Experiments in wild-type male mice showed that continuous infusion of GnRH, in addition to suppressing LH pulsatility, has deleterious effects on both olfactory and cognitive performance (83) (Fig. 3B and 3C). However, continuous administration of GnRH agonists or antagonists is used in the clinic to treat various disorders (Fig. 2D).
Prevot further teaches “Similarly, low testosterone in men has been consistently associated with poor cognitive performance and increased risk of Alzheimer disease. In addition, men receiving androgen deprivation therapy (ie, GnRH agonists) for prostate cancer are not only prone to accelerated cognitive decline, but also have a higher risk of developing dementia and Alzheimer disease. In patients with Alzheimer disease, trials of testosterone or estrogen supplementation have not demonstrated consistent improvements in cognitive function or delay in disease progression. A possible explanation for this failure, particularly regarding initial trials of estrogen replacement, is that the estrogen treatment was begun too late. Yet, considering the study showing a role for GnRH in cognition, this failure could simply be because the estrogen replacement did not reverse the main underlying cause of the decline: the loss of physiological GnRH tone in the brain. Similar to Ts65Dn mice, aged THY::TAU22 mice show normal LH pulse frequency but decreased LH amplitude, and pulsatile GnRH infusion rescues both odor discrimination and object recognition memory (Fig. 4). An alternative but not mutually exclusive hypothesis involves FSH, whose circulating levels increase after gonadectomy and are seemingly elevated in human patients with cognitive disorders, such as men with Down syndrome. Indeed, in 2022, 1 study suggested that FSH, by acting on neuronal FSH receptors in the cerebral cortex and the hippocampus, may accelerate the onset of Alzheimer-like disease in mouse models by inducing the expression of Cebpb. This transcription factor is not only known to repress the Gnrh1 promoter but also to activate the expression of arginine endopeptidase, a delta-secretase that cleaves amyloid precursor protein and Tau, which is thought to favor the onset of Alzheimer disease–like neuropathology. While treatment of ovariectomized Alzheimer mice with FSH-neutralizing antibodies reversed Alzheimer disease–like neuropathology, pulsatile GnRH therapy also reduced FSH levels in men with Down syndrome, 75% of whom are known to develop an Alzheimer-like dementia by 65 years of age. Collectively, these findings strongly suggest that cognitive deficits in dementia-like disorders could be caused by an alteration of GnRH production and its pulsatile release, and that pulsatile GnRH therapy holds promise to improve both cognitive and sensory deficits in neurodegenerative disorders.
Thus, there appears to be a nexus between GnRH production and specific cognitive conditions. However, the predictability is lacking with regards to using GnRH for treatment of any Cognitive defect in patients having both a cognitive disorder and an olfactory dysfunction throughout the full scope of the claims.
The Predictability or Unpredictability of the Art/ The Relative Skill of Those in the Art
As mentioned above, neurological and endocrine interventions in cognition are highly unpredictable. Cognitive improvement varies widely by species, disorder, age, sex and disease stage. Furthermore, the role of GnRH is cognition is not fully elucidated, making outcomes of pulsatile therapy more unpredictable.
Furthermore, because the pathogenesis of each cognitive disorder varies dramatically, the biological effect of GnRH on neuronal circuits and cognition is highly unpredictable. The mechanism through which GnRH influences cognitive and olfactory function in Down syndrome mice cannot be presumed to operate similarly in Alzheimer’s, Parkinson’s or other disorders.
The unpredictable and heterogenous nature of these disorders weight strongly against enablement.
Amount of Guidance/ The Presence or Absence of Working Examples
Applicant’s reduce to practice the following: GnRH Replacement Therapies Reverse Olfactory- and Cognitive-Associated Impairments in Ts65Dn Mice (see paragraph 0079, model for Down syndrome). Example 2 shows that “Acute Chemogenetic Inhibition of GnRH-R Expressing Neurons Impairs Cognitive and Olfactory Performance in Adult Control Mice” (see paragraph 0155). The working example is limited to a single genetic disorder (Down Syndrome) in a non-human species. The claim encompasses a far broader patient population and treatment contexts.
The working examples are limited primarily to Down Syndrome mouse models and chemogenetic inhibition studies in mice. The specification does not provide representative working examples demonstrating treatment of the numerous cognitive disorders encompassed by the claims in patients having olfactory dysfunction, including but not limited to Alzheimers, Parkinsons, vascular dementia ,TBI etc… or idiopathic age associated cognitive decline.
One of ordinary skill in the art would not consider the examples provided in the instant specification to be representative of the full scope of the claimed genus of alleviating, reducing or delaying onset of any cognitive defect in a patient with any cognitive disorder associated with olfactory dysfunction.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed agents would be effective at alleviating, reducing or delaying onset of any cognitive defect in a patient with both a cognitive disorder and an olfactory dysfunction throughout the full breadth of the claims. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation.
Although the specification discusses numerous cognitive disorders and broadly defines olfactory dysfunction, the specification provides no representative examples demonstrating that pulsatile GnRH therapy successfully alleviates cognitive defects across the full scope of combinations encompassed by the claims. Because the etiology, pathology, and mechanisms underlying the claimed cognitive disorders differ substantially, one of ordinary skill in the art would not reasonably expect results obtained in a Down Syndrome mouse model to be predictive of treatment efficacy throughout the entire claimed genus without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Response to Applicant’s Arguments
Applicant argues that the enablement rejection is no longer applicable because claim 1 has been amended to require that the patient have both a cognitive disorder and an olfactory dysfunction, and because the limitation directed to delaying onset has been deleted.
Applicants argument has been fully considered but not found persuasive. The amendment has been considered, but does not overcome the enablement rejection. Although claim 1 now requires a patient having both a cognitive disorder and an olfactory dysfunction, the claims continue to encompass treatment of numerous cognitive disorders and patient populations, including age associated cognitive decline, Down syndrome, and other neurocognitive disorders recited or incorporated by the specification. The specification does not reasonably enable one of ordinary skill in the art to practice the full scope of the claimed invention without undue experimentation. The disclosure remains limited primarily to a Down syndrome mouse model and does not provide sufficient guidance demonstrating that pulsatile GnRH administration alleviates cognitive defects throughout the full scope of the claimed genus of patients having both a cognitive disorder and an olfactory dysfunction.
Applicant argues that the inventor declaration demonstrates that at least some cognitive impairments associated with olfactory dysfunction result from abnormal endogenous GnRH secretion and therefore one of ordinary skill would understand that restoring pulsatile GnRH administration would alleviate cognitive defects.
Applicant’s arguments have been fully considered but not found persuasive. The declaration primarily provides a scientific rationale explaining why GnRH may influence both cognition and olfaction. However, providing a plausible biological mechanism does not establish that the specification enables the full scope of the presently claimed invention. Enablement requires that the specification teach one of ordinary skill how to make and use the claimed invention throughout its full scope without undue experimentation.
Neither the specification nor the declaration demonstrates that pulsatile GnRH administration successfully alleviates cognitive defects across the broad range of claimed cognitive disorders and patients populations recited or encompassed by the claims. Instead, the evidence remains limited to particular experimental systems and does not establish that the claimed therapeutic effect is generally achievable throughout the breadth of the claims.
Applicant argues that post published evidence confirms that one of ordinary skill would have understood from the specification that pulsatile GnRH administration can alleviate cognitive defects associated with olfactory dysfunction.
Applicant’s arguments have been fully considered but not found persuasive. Although post filed evidence may in certain circumstances be considered as evidence of what was known by those skilled in the art at the time of the filing date, it cannot remedy an originally non enabling disclosure or supply missing teachings from the specification. The issue is whether one of ordinary skill in the art could make and use the full scope of the claimed invention without undue experimentation. The post published evidence does not cure the absence of sufficient guidance within the original specification regarding treatment of the full scope of claimed cognitive disorders in patients having olfactory dysfunction.
Applicant argues that the specification is therefore enabling of the claims as presently amended.
Applicant’s arguments have been fully considered but not found persuasive. Even after amendment, the claims encompass treatment of patients having numerous distinct cognitive disorders together with olfactory dysfunction using pulsatile GnRH administration. The specification contains only limited working examples directed primarily to a Down Syndrome mouse model and provides no representative examples demonstrating successful treatment across the breadth of the claimed disorders.
Furthermore, neurological disorders exhibit heterogenous etiologies and mechanisms, and the specification itself acknowledges multiple distinct cognitive disorders. Consequently, substantial experimentation would still be required to determine whether pulsatile GnRH administration would successfully alleviate cognitive defects across the full claimed scope. Considering the wands factors, it is maintained that there would be undue experimentation required.
New 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Dongsheng (WO2014179139 A2) in view of Happ (Fertility and Sterility, Volume 43, No. 4, 1985) as evidenced by CDC (see attached handout), Belchetz (AAAS, 1978, volume 202, 10) and Wilson (Arch. Gen. Psychiatry, 2007).
Dongsheng teaches ”A method of treating an aging effect in a subject comprising administering to the subject gonadotropin-releasing hormone (GnRH) or an analog thereof in an amount that is effective to treat an aging effect in a subject” (see claim 1). Dongsheng teaches wherein the GnRH is administered systemically to the subject (claim 3) and “wherein the aging effect comprises one or more of cognitive decline, muscle loss and/or muscle weakness, and loss of bone mass” (see claim 11) and the subject is elderly (claim 15). The patient population of Dongsheng teaches treatment of cognitive decline in elderly patients (the cognitive disorder being age associated cognitive decline) but does not specifically stated the patients had olfactory dysfunction.
However, Wilson teaches that difficulty identifying odors predicts transition from normal cognition to mild cognitive impairment and further teaches that impaired odor identification is associated with lower baseline cognition and more rapid cognitive decline (see Wilson, page 806, comment). Wilson teaches that in older adults, olfactory dysfunction is associated with cognitive decline and predicts the development of mild cognitive impairment. Thus, Wilson teaches that olfactory dysfunction was recognized clinical characteristic of individuals experiencing or progressing toward cognitive impairment in an elderly population (see Table 1).
Because Wilson teaches that olfactory dysfunction is a recognized clinical characteristic of patients experiencing or progressing toward cognitive impairment (including aging individuals), one of ordinary skill in the art would have found it obvious to apply Dongsheng’s known GnRH treatment for cognitive decline with aging to this recognized subgroup of patients. Doing so merely applies the known treatment to a known subset of the patient population and represents the predictable use of the prior art according to its established function.
It would have been obvious before the effective filing date of the claimed invention to administer Dongsheng’s GnRH treatment to patients having both a cognitive disorder and olfactory dysfunction. One of ordinary skill in the art would have been motivated to do so because Wilson teaches that olfactory dysfunction is associated with cognitive decline in older adults, predicts the subsequent development of MCI, and is associated with lower cognition and rapid cognitive decline. Thus, Wilson identifies patients having both cognitive impairment and olfactory dysfunction as a recognized patient population. Applying the known GnRH treatment taught by Donsheng to this known subgroup of patients would have represented the predictable use of a known treatment for its intended purpose with a reasonable expectation of successfully treating the cognitive disorder (see MPEP 2143, KSR Int’l Co. V. Teleflex Inc., 550 U.S. 398, 2007).
Dongsheng is additionally silent to wherein the GnRH is administered in a manner to reproduced natural GnRH pulsatile peaks observed in control population of same gender as the mammalian patient (pulsatile administration).
Happ teaches GnRH must be administered in a pulsatile manner to restore physiological LH/FSH secretion to avoid pituitary desensitization. Specifically on page 599, introduction, Happ states that pulsatile GnRH therapy mimics natural hypothalamic GnRH pulses and is more physiologic than continual dosing. Happ teaches that a dose of 0.025 ug/kg body weight could be established as a physiological dose (which is 25 ng/kg) as an equivalent to endogenous GnRH dose (see tope of page 604, right column). Happ teaches higher doses of 2, 4 and 8 ug GnRH every 2 ½ hours (see figure 2B). If we assume 50 kg for an average 14 year old body, this would result in 40 ng/kg dosing (for 2 ug) and 50 ng/kg for 4 ug etc... Taken together, Happ emphasizes that continuous or high dose depot GnRH leads to receptor desensitization and is ineffective (see pages 599-601).
Belchetz teaches of foundational studies in hypothalamic lesioned monkeys (see abstract) showing continuous IV GnRH infusion fails to establish gonadotropin secretion (see page 631, left column). Belchetz teaches that intermitted (pulsatile) delivery of 1 ug GnRH every hour leads to robust restoration of levels (see page 632, right panel of Figure 1 and Figure 2). Belchetz attribute the difference to pituitary receptor downregulation during continuous exposure (see page 631, right column).
It would have been obvious before the effective filing date of the claimed invention to administer GnRH in a pulsatile manner in Dongsheng’s method of treating cognitive decline in the elderly with systemic GnRH. One of ordinary skill in the art would have been motivated to do so because Happ and Belchetz teaches that physiological hormone restoration requires pulsatile GnRH administration. Happ shows that doses every two hours restores endocrine function in patients, while Belchetz teaches that continuous GnRH fails and pulsative administration is essential to avoid receptor desensitization. There is a reasonable expectation of success because the goal in Dongsheng is to restore GnRH signaling in the aging brain to promote neurogenesis and cognitive improvement. Delivering GnRH in physiologic (pulsatile) manner would have been recognized as necessary to preserve downstream signaling integrity in both the pituitary and CNS. Furthermore, According to KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), optimization of dosage regimen and delivery mode based on known physiology represents a routine modification that would yield predictable results.
Regarding claim 7, Dongsheng teaches treating age associated cognitive decline (See claims 1, 10-11).
Regarding claim 8, the limitation of “cognitive disorder is an asymptomatic or mild stage”, is obvious under 103 over Dongsheng in view of Happ and Belchetz given Dongsheng directly links early hypothalamic GnRH decline to aging related brain dysfunction and teaches that GnRH therapy promotes neurogenesis and reverses aging disorders (see paragraph 0052), motivating early stage intervention using the pulsatile regimens known in the prior art.
Regarding claim 10, Happ teaches that a dose of 0.025 ug/kg body weight could be established as a physiological dose (which is 25 ng/kg) as an equivalent to endogenous GnRH dose (see top of page 604, right column). Happ teaches higher doses of 2, 4 and 8 ug GnRH every 2 ½ hours (see figure 2B). If we assume 50 kg for an average 14 year old body (as evidenced by CDC, see attached handout), this would result in 40 ng/kg dosing (for 2 ug) and 50 ng/kg for 4 ug etc.... These amounts are used in a pulsatile fashion and is confirmed to restore hormone responsiveness. Accordingly, claim 10 is obvious over Dongsheng in view of Happ and Belchetz.
Regarding claims 9 and 11, Dongsheng teaches wherein the subject can be human (see paragraph 0021) and both males and females were studied (see paragraphs 0045, 0048 and 0051). Nevertheless, it would have been obvious before the effective filing date to administer GnRH in both male and female with aging associated cognitive impairment. One of ordinary skill in the art would have been motivated to do so because they hypothalamic regulation of GnRH is known to occur in both sexes and both male and female mammals exhibit age related cognitive decline linked to GnRH reduction.
Regarding claim 12, While Happ does not recite 75 ug/kg /90 minutes, it does teach using higher doses and the idea of dose/frequency escalation in patients showing insufficient response. Happ teaches a duration of every 153 minutes (see page 600, left column, second paragraph).
It would have been obvious to optimize the dosing interval and amount, particularly in light of Happ’s direct discussion of adjusting both parameters to achieve therapeutic benefit. Therefore, claim 12 is also obvious over Dongsheng in view of Happ and Belchetz. Nevertheless, the dosing and timing of the dosing are considered result effective variables and should be optimized to achieve optimal therapeutic effectiveness (see MPEP 2144.05).
Response to Applicant’s Arguments
Applicant argues that Donsheng does not teach administering GnRH in a manner that reproduces natural GnRH pulsastile peaks observed in a control population of the same gender as the mammalian patient.
Applicant’s argument has been fully considered but not found persuasive. As set forth in the rejection, Dongsheng is relied upon for treating age associated cognitive decline using GnRH. Happ teaches that GnRH should be administered in a pulsatile manner to mimic physiological hypothalamic GnRH secretion and restore endocrine function while avoiding receptor desensitization. Belchetz further teaches that intermittent GnRH administration restores gonadotropin secretion whereas continuous administration fails due to receptor downregulation. One of ordinary in the art would have been motivated to administer Dongsheng’s GnRH treatment in the physiological pulsatile manner taught by Hap and Belchetz because doing so represents the recognized physiological method of GnRH replacement and would have provided a reasonable expectation of success. Optimizing the dosing regimen according to known physiological principles constitutes no more than routine optimization (see MPEP 2144.05).
Applicant argues that none of the applied references teach or suggest treating a patient having both a cognitive disorder and an olfactory dysfunction.
Applicant’s arguments have been fully considered but not found persuasive. Wilson teaches that impaired odor identification (olfactory dysfunction) predicts that subsequent development of mild cognitive impairment in older adults and is associated with lower baseline cognition and more rapid cognitive decline. Wilson further teaches that difficulty identifying odors predicts that transition from normal cognition to mild cognitive impairment and concludes that olfactory dysfunction can be an early manifestation of dementia and cognitive decline. Accordingly, Wilson establishes that older patients exhibiting or progressing toward cognitive impairment and olfactory dysfunction were recognized in the art. Dongsheng teaches treating age associated cognitive decline in elderly patients using GnRH. Therefore, it would have been obvious to administer Dongsheng’s GnRH treatment to the known subgroup of elderly patients having both a cognitive disorder and an olfactory dysfunction. Selecting this recognized patient subgroup merely represents the predictable application of the known treatment to patients exhibiting known clinical characteristics and would have provided one of ordinary skill in the art with a reasonable expectation of success.
Applicant argues that there is no motivation to combined the cited references.
Applicant’s arguments have been fully considered but not found persuasive. Dongsheng teaches GnRH treatment for age associated cognitive decline. Happ and Belchetz teach the physiological GnRH replacement requires pulsatile administration to mimic endogenous GnRH secretion and prevent receptor desensitization. Wilson teaches that olfactory dysfunction is associated with cognitive decline in older adults and predicts the development of mild cognitive impairment. One of ordinary skill in the art would have been motivated to combine these teachings to administer physiologically appropriate pulsatile GnRH therapy to the recognized population of elderly patients having cognitive decline, including those exhibiting olfactory dysfunction. The combination merely applies known techniques to improve the same therapy in a known patient population and represents the predictable use of prior art elements according to their established functions (see KSR, 2143).
Applicant relies on the Declaration to assert that the inventors discovered an association between GnRH deficiency, olfactory dysfunction, and cognitive impairment, and that pulsatile GnRH alleviates cognitive impairment associated with olfactory dysfunction.
Applicant’s arguments have been fully considered but not found persuasive. The Declaration is acknowledged but is not persuasive of nonobviousness. The applied prior art does not rely upon the same biological mechanism proposed by Applicant. Rather, obviousness is based upon the combined teachings of Dongsheng, Happ, Belchetz, and Wilson, which collectively teach treating age associated cognitive decline and GnRH, administering GnRH in a physiological pulsatile manner, and recognizing olfactory dysfunction as a clinical characteristic associated with cognitive decline in older adults. The claims do not require any particular mechanism by which GnRH produces the therapeutic effect. Therefore, the Declaration does not outweigh the evidence supporting the prima facie case of obviousness.
Claim(s) 1, 7-13 are rejected under 35 U.S.C. 103 as being unpatentable over Dongsheng (WO2014179139 A2) in view of Happ (Fertility and Sterility, Volume 43, No. 4, 1985) as evidenced by CDC (see attached handout), Belchetz (AAAS, 1978, volume 202, 10) as applied to claims 1, 7-12) and Wilson (Arch. Gen. Psychiatry, 2007) above in further view of DrugBank (Gonadorelin, Uses, Interactions and Mechanism of action, published online 2005, cited previously).
The teachings of Dongsheng, Happ, Belchetz and Wilson are described in the above rejection.
The combined references of Dongsheng, Happ, Belchetz and Wilson are silent to wherein the GnRH is gonadorelin. However, Gonadorelin is the synthetic form of GnRH that is often use to increase GnRH secretion (see attached handout from Drug bank). Drugbank teaches that “Gonadorelin is another name for gonadotropin-releasing hormone (GnRH). It is a synthetic decapeptide prepared using solid phase peptide synthesis. GnRH is responsible for the release of follicle stimulating hormone and leutinizing hormone from the anterior pituitary” (see background).
Therefore, it would have been obvious to try gonadorelin as the pulsatile GnRH of Dongsheng, Happ, Belchetz and Wilson given that it is synonymous for GnRH.
It has been held that under KSR that “obvious to try” may be an appropriate test under 103. The Supreme Court stated in KSR, When there is motivation “to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727,_,82 USPQ2d 1385, 1397 (2007).
The skilled artisan would have had reason to try gonadorelin with the reasonable expectation that it would be successful. It would be obvious to try using gonadorelin as the GnRH given that it is known in the art for that purpose (an it is GnRH) and has been shown to effectively have the same properties of GnRH. Thus, use of the synthetic GnRH gonadorelin is “the product not of innovation but of ordinary skill and common sense,” leading to the conclusion that invention is not patentable as it would have been obvious.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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