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
The amendment to the claims filed after non-final office action on June 18, 2025 is acknowledged. Claims 1-3 were amended, claims 5-6, 22-32 were canceled, claims 33-37 were newly added and claims 1-4, 7-21, 33-37 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL previously. Claims 4, 7-21 remain withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-3, 33-37 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of claims 1-3 and 5-6 under 35 U.S.C. 102(a)(1) as being anticipated by Crowley (WO2007084211, cited in Applicant’s IDS) is withdrawn in view of amendment of the claims filed June 18, 2025.
The rejection of claims 1, 3 and 5 under 35 U.S.C. 102(a)(1) as being anticipated by Chen (J Clin Endocrinol Metab, December 2014, 99(12):E2762–E2771) is withdrawn in view of amendment of the claims filed June 18, 2025.
The objection to claim 6 is withdrawn in view of amendment of the claims filed June 18, 2025.
The rejection of claim 2 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the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is withdrawn in view of amendment of the claims filed June 18, 2025.
Maintained/Revised Rejections
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 1-3 and 33-37 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 acute short term bolus or infusion of KP-10 at physiologic and supraphysiologic doses, does not reasonably provide enablement for long term dosing, treatment of any PHH etiology at supraphysiologic dosing and all Kisspeptin isoforms. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and 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/Breadth of the claims
The claims are now drawn to “A method of treating a human subject with pathologic hypogonadotropic hypogonadotropism (PHH) by administering a plurality of doses of kisspeptin, wherein the plurality of dose comprise at least one supraphysiologic dose equivalent to 2.4-24 nmol/kg KP-10.” Claim 2 requires at least administration at 1-6 hours and claims 33-35 range from hours to 12 months. Claim 3 encompasses 0.08-2.4 nmol/kg kisspeptin-10 equivalent via IVB. The claims encompass all kisspeptin isoforms (KP-10, 13, 14, 54 etc…) administered at specific supraphysiologic dose ranges, in all PHH etiologies (congenital, genetic, functional, acquired), and over short term and long term regiments.
The claims encompass a broad patient population (all etiologies of PHH, including genetic variants such as TAC3/TACR3, IHH and Kallmann syndrome). The claims further encompass wide dosing regiments (supraphysiologic doses and multiple doses) and extended treatment duration (over 2-3 days and up to 12 months). The scope extends beyond acute testing and single etiology, and instead covers chronic therapeutic use across multiple mechanistically distinct forms of PHH.
The State of the Prior Art and the predictability or unpredictability of the art
The prior art and Applicant’s own data demonstrate that the field of Kisspeptin biology is high unpredictable. Matsui (see attached handout) and others show paradoxical suppression of LH and testosterone following chronic administration of kisspeptin analogs in animals (see title, abstract).
Lippincott* (see attached handout, 2018) teaches “Kisspeptin stimulates GnRH-induced LH secretion in healthy volunteers and in patients with congenital hypogonadotropic hypogonadism who have undergone reversal (spontaneous recovery of the reproductive cascade) (see page 1294, second paragraph). In addition, kisspeptin stimulates LH secretion in patients with acquired hypogonadotropism (hypothalamic amenorrhea). However, kisspeptin fails to stimulate LH release in patients with abiding hypogonadotropic hypogonadism (no reversal) (page 1294, second paragraph).
Lippincott* teaches “Despite all of these factors, these patients with IHH (six male and one female), once sex steroid replete, did not show a response to exogenous kisspeptin. Stated alternatively, a normalized sex steroid milieu was not capable of overcoming the kisspeptin resistance (simply meaning a failure to respond to exogenous administration of the peptide) of these patients. Because the administration of kisspeptin should bypass any abnormalities in the synthesis or secretion of kisspeptin itself or any factors upstream from kisspeptin, it is possible that the inability to respond to exogenous kisspeptin is due to problems further downstream. These include, but are not limited to, abnormalities in kisspeptin receptor synthesis, expression, trafficking, or downstream signaling. The latter could include abnormalities in second-messenger signaling systems within GnRH neurons related specifically to kisspeptin, abnormalities within GnRH neurons completely unrelated to kisspeptin signaling, or a problem related to other cofactors/neurotransmitters that affect GnRH neuronal synchronization” (see Discussion, last paragraphs).
George (2012, see attached handout) show dose dependent but variable LH responses in healthy men, with diminished responses at higher doses. George and Young (see attached reference) show that patients with TAC3/TACR3 mutations respond inconsistently; some increase LH pulse frequency while others do not respond. Kallmann patients frequent fail to respond to kisspeptin at any dose reflecting a fundamental impairment of GnRH neuronal function (see George, end of page 2).
Given the variability and lack of predictability, one of skill would not have a reasonable expectation of success across the full breadth of patient populations and dosing regimens as claimed.
The Relative Skill of Those in the Art
While those of ordinary skill in reproductive endocrinology would be familiar with GnRH stimulation tests, LH/FSH assays, and animal models of hypogonadism, the art lacks predictable guidance on which patients would respond to kisspeptin, the appropriate supraphysiologic dosage range for efficacy, whether chronic administration could safely or effectively restore reproductive function. Thus, even a skill artisan could not extrapolate from the limited, acute examples to the broad chronic therapeutic claims without undue experimentation.
Amount of Guidance/ the Presence or Absence of Working Examples
Example 1 uses kisspeptin to Predict Pubertal Outcomes for Youth with Pubertal Delay. Example two looks at Supraphysiologic Kisspeptin-10 to Improve Pubertal Outcomes for Youth with Pubertal Delay that were diagnosed with IHH (see paragraph 0015). Example 2: One youth with pubertal delay/IHH received .313 ug/kg KP-10 without effect, but later responded to a single 18 ug/kg dose. This is isolated instance suggests supraphysiological dosing may overcome “kisspeptin resistance” but it is a single subject, single bolus and not reproducible or generalized.
Example 3: Four sisters with TAC3/TACR3 administered by infusion (1.5 ug/kg/hr x 11 hours) (this is from a previously published study, see paragraph 0121). Some TAC3 patients showed increased LH pulses awhile TACR3 patients did not. Variability persisted despite repeated exposures. Tables 6- present individual hormone values before and after KP-10. Results are in consistent, small sample and acute only. NO examples demonstrate chronic administration over weeks or months, nor do they confirm efficacy in Kallmann syndrome.
In paragraph 0129, Applicants discuss a 2016 study of subjects 1, 3, 4-5 wherein it was determined if LH pulse could be modified with KP-10 (Figures 8-10).
Applicants further state “To corroborate the findings in IHH patients, we conducted experiments in Tac2 KO and WT control female mice. Peripheral administration of kp-10 elicited a robust increase in LH in all animal groups regardless of age and genotype. Interestingly, peripubertal Tac2 KO female mice, lacking NKB, displayed a higher magnitude of LH release (5.29±0.43 ng/ml, n=5) than control females (2.67±0.48 ng/ml, n=5; p<0.01) (FIG. 11). However, LH returned to baseline faster in Tac2 KO mice (52±3.72 min after injection, n=5) than in WT control (68±3.72 min, n=5; p<0.01). Adult WT mice displayed the expected LH pulse in response to kp-10, while the Tac2 KO mice that responded to kp-10 showed a bi-phasic response, displaying two overlapping peaks of LH (FIG. 10). In both adult groups, the induction of LH release appeared more sustained than in peripubertal mice (peripubertal WT: 68±3.742 min, n=5 vs adult WT142.5±4.78 min after injection, n=4, p<0.0001; peripubertal Tac2 KO: 52±3.742, n=5 vs adult Tac2 KO 156.7±3.33 min, n=3, p=0.07)” (see paragraph 0163).
Thus, while the disclosure provides illustrative acute dosing regimens (from previous studies), it lacks enabling detail for chronic dosing, for the entire claimed dose range and for all etiologies encompassed by the claim.
The Quantity of Experimentation Necessary
Given the variability in patient response, the absence of guidance for chronic therapy, and the lack of examples across the full breadth of PHH etiologies a skilled artisan would need to engage in extensive clinical experimentation to determine whether supraphysiologic kisspeptin 10 dosing could treat all forms of PHH, especially idiopathic and Kallmann syndrome. Such experimentation would require testing of dose, frequency and duration in multiple patient populations which is more than routine optimization which constitutes undue experimentation.
Response to Applicant’s Arguments
Applicant argues “Without assenting to the rejection and solely in an effort to expedite prosecution, independent claim 1 has been amended to remove reference to a "reproductive endocrine dysfunction" and a "kisspeptin analog". The claims are now directed to a method of treating a human subject who has pathologic hypogonadotropic hypogonadotropism by administering kisspeptin, which the Examiner acknowledges is enabled by the present specification. Withdrawal of this rejection is respectfully requested.
Applicants arguments have been fully considered but not found persuasive. Although the specification includes certain examples demonstrating kisspeptin administration in limited patient populations (small scale studies in IHH, or specific genetic backgrounds TAC2/TAC3 mutations) the disclosure is insufficient to enable the full scope of the present claims.
The claims as amended continue to cover treatment of all forms of pathologic hypogonadotropic hypogonadotropism with kisspeptin, across a wide spectrum of durations (e.g. at least 2-3 days, at least 1-12 months”) and across diverse patient groups (idiopathic, kallmann syndrome, other genetic or acquired etiologies).The specification, however, provides only a few examples in highly specific contexts and does not establish that such treatment is operable across the full breadth of the claims.
As demonstrated by the variability in clinical results reported in the art (e.g., some IHH patients responding to kisspeptin while others not; evidence of tachyphylaxis/desensitization with repeated dosing), the filed is unpredictable. The specification does not provide sufficient guidance to predict dosing regiments, patient selection, or long term effectiveness across the broad PHH population encompassed by the claims.
Given this unpredictability, a person of ordinary skill in the art would need to engage in extensive clinical experimentation to determine which forms of PHH are responsive to kisspeptin treatment, what dosing regimens are effective over extended periods (weeks to months), and whether tachyphylaxis or resistance can be overcome. Such experimentation exceeds routine optimization and constitutes undue experimentation. Therefore, even with the amendment of claim 1, the specification fails to enable the full scope of the claims without undue experimentation.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 33-37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a dose equivalent to 2.4-24 nmol/kg kisspeptin-10”, but the term “equivalent” is ambiguous. It is unclear whether equivalence refers to molar equivalence of another kisspeptin isoform, pharmacologic equivalence (same biologic activity) or some other undefined measure. Because the specification does not provide guidance on how equivalence is determined, one of ordinary skill in the art cannot ascertain with reasonable certainty the scope of the claimed invention. Claims 2-3, 33-37 are also rejected due to their dependence on claim 1 and not further clarifying this point of confusion.
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) 1-3, 33, 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lippincott (J Clinc Endocrinol Metab 101:3061-3069, 2016) .
Regarding claims 1 and 36, Lippincott teaches administration of Kisspeptin-10 to human subjects with idiopathic hypogonadotropic hypogonadism (IHH), including those who have undergone reversal of their condition. Lippincott teaches a plurality of intravenous doses (boluses) of kisspeptin 1o at .24, .72 and 2.4 nmol/kg (see abstract, see also figure 1). Lippincott teaches that kisspeptin responsiveness may underlie reversal of IHH, suggesting that kisspeptin can be used to stimulate hypothalamic pituitary gonadal axis in this patient population. Thus, Lippincott teaches the patient population (PHH/IHH patients), the use of kisspeptin 10 and the administration of a supraphysiological dose (2.4 nmol/kg). Lippincott also shows that the higher dose resulted in a longer response (see Figure 1A for example).
It would have been obvious to before the effective filing date of the claimed invention to administer Kisspeptin 10 to IHH patients, including those with reversal, as taught by Lippincott, and to begin treatment with the supraphysiologic dose, in order to maximize the likelihood of stimulating LH release in patients who may fail to respond to lower doses and also a longer sustained response as taught by Lippincott. Lippincott explicitly teaches that responsiveness to kisspeptin correlates to recovery of the reproductive axis in IHH reversal patients, providing motivation to use kisspeptin as a treatment. There is a reasonable expectation of success given that Lippincott already teaches measurable LH with the higher supraphysiological dose of kisspeptin-10 and that the duration was longer with the higher dose.
Regarding claim 2, Lippincott teaches the plurality of doses administered within the 1-6 interval (see Figure 1, subject 1, administered at hour 1, 4, 7 and 10).
Regarding claim 3, Lippincott teaches IV bolus administration of .24-2.4 nmol/kg KP-10.
Regarding claim 33, Lippincott teaches the plurality of doses administered within the 1-6 interval (see Figure 1, subject 1, administered at hour 1, 4, 7 and 10, three hour interval). In subject 4, the interval is every 2 hours (see figure 1). A person of ordinary skill would have recognized that the varying the interval length is a matter of dosing schedule optimization (routine optimization).
Claim(s) 1 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Jayasena (J Clinc Endocrinol Metab 101:3061-3069, 2016) .
Jayasena teaches a method of administering KP-54 (6.4 nmol/kg) to women with hypothalamic amenorrhea (HA) (See abstract, page 846, “Study 3”). Jayasena teaches that Hypothalamic amenorrhea (HA) is a form of hypogonadotropic hypogonadism and meets the limitations of pathological (see page 840, right column, last two lines). Regarding claim 1, Jayasena meets the limitations of treating pathologic hypogonadotropic hypogonadism comprising administering a plurality of doses of kisspeptin (in particular, KP-54). Regarding dosing, on a molar basis, the amount of 6.4 nmol/kg falls within the claimed “equivalent” dosing window of 2.4-24nmol/kg KP-10.
Regarding claims 34-35, Jayasena teaches a method of administering KP-54 twice weekly for eight weeks total thus meeting the limitations of instant claim 35 (two months) and at least 2-3 days in instant claim 34. During each visit, a subcutaneous injection of either saline or KP-54 was administered to each subject, in a double-blinded manner. After the first injection of saline or KP-54, blood samples were collected at various time points from each subject for 4 h as described above. This 4-h sampling protocol was repeated at 2, 4, and 6 weeks and on the final day of the study protocol at 8 weeks (see page 846, study 3).
Regarding dosing, on a molar basis, the amount of 6.4 nmol/kg falls within the claimed “equivalent” dosing window of 2.4-24nmol/kg KP-10. Thus, Jayasena’s disclosure of supraphysiologic kisspeptin doses in HA patients squarely overlaps the claimed numeric dosing, satisfying the “equivalent to 2.4-24 nmol/kg kP-10” limitation regardless of whether KP-10 itself was administered.
Nevertheless, it would have been obvious before the effective filing date of the claimed invention to administer kisspeptin at a dose equivalent to 2.4-24 nmol/kg kisspeptin-10 in patients with PHH. Jayasena teaches administration of 6.4 nmol/kg of KP-54 to women with hypothalamic amenorrhea, a form of PHH, and demonstrates stimulation of LH and FSH release. Although Jayasena discloses KP-54 rather than KP-10, a person of ordinary skill would have recognized that KP-10 is the minimal biologically active C-terminal fragment of KP-54 that binds the same receptor and elicits the same downstream stimulation. Because Jayasena’s disclose dose of 6.4 nmol/kg KP-54 falls directly within the claimed “equivalent to 2.4-24 nmol/kg KP-10” range, it would have been an obvious variation to substitute KP-10 for KP-54 at an equivalent molar dosage, with a reasonable expectation of success that the shorter fragment would likewise stimulate gonadotropin release in the same patient population.
A person of ordinary skill in the art would recognize that equivalent molar dosing of either peptide stimulates GnRH release in HA (PHH) patients thus rendering obvious the instant claims. There is a reasonable expectation of success because both act on the same receptor, and Jayasena demonstrated the efficacy of that dosing.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
/JULIE HA/Primary Examiner, Art Unit 1654