Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The first preliminary amendment filed 08/10/2023 is acknowledged. Claims 1 and 3-18 are amended. No restriction is being imposed in this case. Claims 1-20 are pending and under examination.
Effective Filing Date
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) and 365(c) are acknowledged. No foreign priority claims are made. Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims is supported by the disclosure in PCT/US2022/018517 and provisional application serial no. 63/155,690. The effective filing date of claims 1-20 is 03/02/2021.
Claim Rejections - 35 USC § 112b
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 10, 16, and 20 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.
In the context of claims 10, 16, and 20, the phrase "optionally" reads as an exemplary term. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Therefore, claims 10, 16, and 20 are rejected under 35 U.S.C. 112(b) for being indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 10 are rejected under 35 U.S.C. 102a1 as being anticipated by NIH Grant 1I21RX001371-01.
Independent claim 1 is drawn to a method of inducing cognitive recovery in a subject, comprising administration of human chorionic gonadotropic (hCG), luteinizing hormone (hLH), or a combination thereof. Claim 10 further limits the method of claim 1 to an administration timeline of about one month to about 18 months.
1I21RX001371-01 discloses administering hCG to subjects suffering from TBI to enhance neurogenesis and stimulate cognitive recovery (claim 1), and that subjects would be treated for 6 months (claim 10) [see Specific Aim 1].
Because 1I21RX001371-01 discloses administration of hCG to induce cognitive recovery after TBI, the same clinically significant improvements as recited in claims 1 and 10 must have been inherently occurring in the prior art of 1I21RX001371-01, see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); also, Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846); i.e., the treatment methods set forth in 1I21RX001371-01 must, by definition achieve the same clinically significant improvements as recited in claims 1 and 10, absent evidence to the contrary. Thus, the limitations of claims 1 and 10 are met by 1I21RX001371-01.
Therefore, claims 1 and 10 are rejected under 35 U.S.C. 102a1.
Claims 1, 7, 8, 11, and 16 are rejected under 35 U.S.C. 102a1 as being anticipated by Zygun (2010).
Zygun discloses administration of hCG every other day for a total of 3 doses [see p.8, Intervention/treatment], which is equivalent to every other day for one week (claims 7 and 8), to male patients ages 18-65 [see p. 5, Inclusion Criteria, point 1; p. 8, Intervention/treatment] and to women “of child bearing potential,” [see p.5, Inclusion Criteria, point 6-2] which necessarily means pre-menopausal (claim 16), following TBI [see p.5, Inclusion Criteria, point 3] (claim 1) . Further, Zygun discloses administration of hCG at 10,000 IU per dose. CDC health statistics using data gathered from 2015-2018 estimate that the average woman’s weight in the United States during that time was about 76kg [see p.7] and about 90kg for men [see p.9]. This corresponds to Zygun administering about 130 IU/kg to human female subjects and 111 IU/kg to human males (claim 11) (of note, MPEP 2131.10 permits 102 rejection over multiple references when the references are cited to show that a characteristic not disclosed is inherent). As discussed above, given that Zygun discloses administration of hCG and hLH to induce cognitive recovery following TBI, the treatment methods must, by definition achieve the same clinically significant improvements as recited in the instant application, absent evidence to the contrary.
Therefore, claims 1, 7, 8, 11, and 16 are rejected under 35 U.S.C. 102a1.
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.
Claims 1, 5, 10, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over NIH Grant 1I21RX001371-01.
1I21RX001371-01 discloses administering hCG to subjects suffering from TBI to enhance neurogenesis and stimulate cognitive recovery (claim 1), and that subjects would be treated for 6 months (claim 10) [see Specific Aim 1]. Because 1I21RX001371-01 discloses administration of hCG to induce cognitive recovery following TBI, the same clinically significant improvements as recited in claims 1-20 must have been inherently occurring in the prior art of 1I21RX001371-01.
1I21RX001371-01 does not disclose the specific sequences claimed or 90% thereof, or specifically disclose that the subjects are capable of normal adult gonadal hormone synthesis and secretion.
The sequences recited in claim 5 of the instant application encode the native human alpha and beta subunits of hCG and hLH. hCG and hLH are well characterized proteins with subunit sequences that were publicly known at the time of the invention. More specifically, SEQ ID NO: 1 was available as of May, 2009 [see UniprotKB: C0KRQ8], SEQ ID NO: 2 as of July, 2015 [see UniprotKB: A0A0F7RQP8] and SEQ ID NO: 3 as of March 2002 [see UniprotKB: Q8WXL0]. It would have been obvious to use the method of 1I21RX001371-01 with native alpha and beta subunits as it was routine in clinical and experimental practice to do so (claim 5).
Furthermore, 1I21RX001371-01 does not limit administration to subjects exhibiting hypogonadism nor does it exclude subjects having normal circulating gonadal hormone levels. Thus, because the grant administers hCG broadly to TBI subjects without limitation, one of ordinary skill in the art would reasonably assume that the subject population necessarily encompasses TBI subjects having normal gonadal hormone levels, and selecting this subset of subjects from the broader population would have been obvious without evidence that hormonally normal subjects would respond differently (claim 15).
Therefore, claims 1, 5, 10, and 15 are rejected under 35 U.S.C. 103.
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over NIH Grant 1I21RX001371-01 as applied to claims 1, 5, 10, and 15 above, and further in view of Barton et al.
1I21RX001371-01 discloses administering hCG to subjects suffering from TBI to enhance neurogenesis and stimulate cognitive recovery (claim 1), and that subjects would be treated for 6 months (claim 10) [see Specific Aim 1].
1I21RX001371-01 fails to teach a method wherein the subject suffers from hypogonadotropic hypogonadism (HH), a TBI associated impairment induced by an injury to the hypothalamus or pituitary gland, or impairment induced by suppression of synthesis and secretion of hormones produced by the hypothalamic-pituitary-gonadal (HPG) axis.
Barton et al. discloses that individuals suffering from traumatic brain injury frequently develop HH [see p.2 paragraph 1] (claim 2), which is characterized by low testosterone levels [see p.2 Introduction] and low or inappropriately normal gonadotropin levels [see p.7 paragraph 4], demonstrating dysfunction of the HPG axis (claim 4). Furthermore, Barton et al. explain that HH frequently results from damage to the pituitary gland [p. 8 paragraph 1] (claim 3). Given this, it would have been obvious to one of ordinary skill in the art to combine the disclosure of 1I21RX001371-01 of administering hCG to subjects suffering from TBI with the teachings of Barton et al., to restore gonadal hormone function in individuals with a hypothalamus injury, a pituitary gland injury, or impaired HCG axis following TBI. Furthermore, there would be a reasonable expectation of success as one would understand that administering hCG to TBI patients with low gonadotropin levels would have the effect of stimulating the gonads to produce normal gonadal hormones.
Therefore, claims 1-5, 10, and 15 are rejected under 35 U.S.C. 103.
Claims 1, 6-9, 11-13, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Zygun in view of Lee et al.
Zygun discloses administration of hCG every other day for a total of 3 doses [see p. 8, Intervention/treatment], which is equivalent to every other day for one week (claims 7 and 8), to male patients ages 18-65 [see p. 5, Inclusion Criteria, point 1; p. 8, Intervention/treatment] and to women “of child bearing potential,” [see p.5, Inclusion Criteria, point 6-2] which necessarily means pre-menopausal (claim 16), following TBI [see p.5, Inclusion Criteria, point 3] (claim 1) . Further, Zygun discloses administration of hCG at 10,000 IU per dose. CDC health statistics using data gathered from 2015-2018 estimate that the average woman’s weight in the United States during that time was about 76kg [see p.7] and about 90kg for men [see p.9]. This corresponds to Zygun administering about 130 IU/kg to human female subjects and 111 IU/kg to human males (claim 11). Given that Zygun discloses administration of hCG and hLH to induce cognitive recovery following TBI, the treatment methods must, by definition achieve the same clinically significant improvements as recited in the instant application, absent evidence to the contrary.
Zygun fails to teach the administration lengths and frequencies of claims 6 and 9, the effective amounts of claims 12 and 13, or that subjects are not capable of normal adult gonadal hormone synthesis and secretion and are further administered a gonadal hormone.
Lee et al. disclose several administration protocols, including administering hCG two to three time per week [see p. 3 paragraph 1] (claim 6) and a regimen comprising administering testosterone replacement therapy (TRT) to hypogonadal men and periodically cycling TRT off and replacing it with 3000IU of hCG every other day for four weeks [see p. 2 paragraph 7] (claims 9, 12, 13, 17, and 18).
Regarding claims 12 and 13, the specification defines an “effective amount” to include dosages that yield acceptable therapeutic effects, and notes that dosages may be adjusted based on the interval of administration. Accordingly, Lee et al. administering 3,000IU hCG every other day for 4 weeks corresponds to an effective amount of about 42,000IU, or 466IU/KG for a 90kg human male, falling within the scope of the claims because the total effective exposure, in light of the specification’s interval guidance, achieves an effective amount.
Regarding claims 17 and 18, the specification defines subjects not capable of normal adult gonadal hormone synthesis and secretion as those having circulating gonadal hormone concentrations outside the normal adult reference ranges. Lee et al. expressly discloses administering testosterone and hCG to men with hypogonadism, which necessarily requires reduced gonadal hormone synthesis and secretion, thereby satisfying the limitations of claims 17 and 18 in light of the specification’s definition of “not capable.”
Furthermore, although Lee et al. discloses these administration schedules and diagnostic steps in the context of reproductive health, this demonstrates that hCG was routinely administered according to repeated dosing schedules over multi-week treatment periods and that administration of hCG could be paired with a gonadal hormone such as testosterone. As such, it would have been obvious for a person of ordinary skill in the art to combine the disclosure of Zygun of administering hCG to subjects suffering from TBI, with the teachings of Lee et al. administering hCG according to a known and routine administration timeline, to subjects suffering from TBI. Additionally, it would have been obvious to further administer a gonadal hormone, such as testosterone, to subjects not capable of normal adult gonadal hormone synthesis and secretion with a reasonable expectation that it would increase circulating gonadal hormone levels, as testosterone replacement therapy was a routine standard of care.
Therefore, claims 1, 6-9, 11-13, and 16-18 are rejected under 35 U.S.C. 103.
Claims 1, 7, 8, 11-13, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Zygun in view of in view of Gulekli et al.
Zygun discloses administration of hCG every other day for a total of 3 doses [see p.8, Intervention/treatment], which is equivalent to every other day for one week (claims 7 and 8), to male patients ages 18-65 [see p. 5, Inclusion Criteria, point 1; p. 8, Intervention/treatment] and to women “of child bearing potential,” [see p.5, Inclusion Criteria, point 6-2] which necessarily means pre-menopausal (claim 16), following TBI [see p.5, Inclusion Criteria, point 3] (claim 1) . Further, Zygun discloses administration of hCG at 10,000 IU per dose. CDC health statistics using data gathered from 2015-2018 estimate that the average woman’s weight in the United States during that time was about 76kg [see p.7] and about 90kg for men [see p.9]. This corresponds to Zygun administering about 130 IU/kg to human female subjects and 111 IU/kg to human males (claim 11).
Zygun fails to teach the effective amounts of claims 12 and 13.
Gulekli et al. disclose administration of hCG to female patients at doses of 10,000 IU up to 20,000 IU to stimulate gonadal hormone production [see abstract]. Using an average adult female body weight of 77kg as discussed above, a 20,000 IU dose of hCG corresponds to approximately 260 IU/kg (claim 12) but slightly below the claimed range of 300-500 IU/kg. However, lighter subpopulations of women, such as Asian women with an average weight of 61kg [see CDC, p.7], would receive 328 IU/kg, which falls within the claimed range of 300-500 IU/kg (claim 13). Regardless, given that the specification defines “about” to be plus or minus 10%, in addition to the routine nature of dose optimization in the art, it would have been obvious to a person of ordinary skill to adjust the administration amounts to fall within the range of 300-500 IU/kg.
Therefore, claims 1, 7, 8, 11-13, and 16 are rejected under 35 U.S.C. 103.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Zygun in view of Lee et al., as applied to claims 1, 6-9, 11-13, and 16-18 above, and further in view of McCullers et al. (01/2002) and McCullers et al. (08/2002).
Zygun discloses administration of hCG every other day for a total of 3 doses [see p.8, Intervention/treatment], which is equivalent to every other day for one week (claims 7 and 8), to male patients ages 18-65 [see p. 5, Inclusion Criteria, point 1; p. 8, Intervention/treatment] and to women “of child bearing potential,” [see p.5, Inclusion Criteria, point 6-2] which necessarily means pre-menopausal (claim 16), following TBI [see p.5, Inclusion Criteria, point 3] (claim 1) . Further, Zygun discloses administration of hCG at 10,000 IU per dose. CDC health statistics using data gathered from 2015-2018 estimate that the average woman’s weight in the United States during that time was about 76kg [see p.7] and about 90kg for men [see p.9]. This corresponds to Zygun administering about 130 IU/kg to human female subjects and 111 IU/kg to human males (claim 11). Lee et al. disclose several administration protocols, including administering hCG two to three time per week [see p. 3 paragraph 1] (claim 6) and a regimen comprising administering testosterone replacement therapy (TRT) to hypogonadal men and periodically cycling TRT off and replacing it with hCG every other day for four weeks [see p. 2 paragraph 7] (claims 9, 12, 13, 17, and 18).
Zygun and Lee et al. fail to disclose the use of RU-486.
McCullers et al. (01/2002) disclose that pretreatment with RU-486, a glucocorticoid receptor antagonist, protects hippocampal neurons following TBI [see, Abstract], indicating that administration of RU-486 is known to mitigate glucocorticoid-mediated neural injury associated with TBI and could improve neurobehavioral outcomes (i.e., information processing, perceptual functioning, and memory) [see, Conclusion]. McCullers et al. (08/2002) discloses that TBI alters glucocorticoid receptor expression and regulation in the hippocampus [see p. 47, section 4.4]. Taken together, it would have been obvious to one of ordinary skill in the art to administer RU-486 to a subject suffering from TBI with a reasonable expectation that it would mitigate glucocorticoid-mediated hippocampal injury and preserve the neurological pathways relevant to cognitive function. Furthermore, one of ordinary skill in the art would have been motivated to administer RU-486 in combination with hCG and/or hLH to address multiple hormonal pathways known to contribute to neurological injury following TBI. Such a combination represents predictable use of known agents for treating the same condition and does not require any synergistic effects.
Therefore, claims 1, 6-9, 11-14, and 16-18 are rejected under 35 U.S.C. 103.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over NIH Grant 1I21RX001371-01 as applied to claims 1, 5, 10, and 15 above, and further in view of Lopez-Rodriguez et al.
1I21RX001371-01 discloses administering hCG to subjects suffering from TBI to enhance neurogenesis and stimulate cognitive recovery (claim 1), and that subjects would be treated for 6 months (claim 10) [see Specific Aim 1]. Because 1I21RX001371-01 discloses administration of hCG to induce cognitive recovery following TBI, the same clinically significant improvements as recited in claims 1-20 must have been inherently occurring in the prior art of 1I21RX001371-01. 1I21RX001371-01 further states “that the stress from a TBI has been shown to markedly suppress circulating gonadotropin and sex steroid concentrations. Moreover, there is indirect evidence that the actions of these hormones are compromised following TBI, since the rampant oxidative stress associated with TBI inhibits steroidogenic enzyme function, leading to a neurosteroid deficient state” [See abstract].
1I21RX001371-01 fails to disclose a method of determining that the subject is capable of normal adult hormone synthesis and secretion.
Lopez-Rodriguez discloses that TBI alters circulating gonadal hormone levels, utilizing a method comprising collecting blood from a subject, extracting plasma, measuring testosterone ranges [see p. 3985, Quantitative Analysis of Neuroactive Steroids”], and comparing to a control sample to determine if levels fall below control ranges [see p. 3987, Figures A, B, and C]. These deficits are associated with poorer outcomes [see p. 3991, paragraph 3]. Thus, a person having ordinary skill in the art would have been motivated to measure circulating gonadal hormones, as described by Lopez-Rodriguez, to evaluate endocrine dysregulation after TBI and provide more precise therapeutic interventions.
Therefore, claims 1, 5, 10, 15, and 19 rejected under 35 U.S.C. 103.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Zygun in view of Lee et al., as applied to claims 1, 6-9, 11-13, and 16-18 above, and further in view of Carnegie.
Zygun discloses administration of hCG every other day for a total of 3 doses [see p.8, Intervention/treatment], which is equivalent to every other day for one week (claims 7 and 8), to male patients ages 18-65 [see p. 5, Inclusion Criteria, point 1; p. 8, Intervention/treatment] and to women “of child bearing potential,” [see p.5, Inclusion Criteria, point 6-2] which necessarily means pre-menopausal (claim 16), following TBI [see p.5, Inclusion Criteria, point 3] (claim 1) . Further, Zygun discloses administration of hCG at 10,000 IU per dose. CDC health statistics using data gathered from 2015-2018 estimate that the average woman’s weight in the United States during that time was about 76kg [see p.7] and about 90kg for men [see p.9]. This corresponds to Zygun administering about 130 IU/kg to human female subjects and 111 IU/kg to human males (claim 11). Lee et al. disclose several administration protocols, including administering hCG two to three time per week [see p. 3 paragraph 1] (claim 6) and a regimen comprising administering testosterone replacement therapy (TRT) to hypogonadal men and periodically cycling TRT off and replacing it with hCG every other day for four weeks [see p. 2 paragraph 7] (claims 9, 12, 13, 17, and 18).
Zygun and Lee et al. fail to disclose a step comprising determining that the subject is not capable of normal adult gonadal hormone synthesis and secretion.
Carnegie teaches a method of diagnosing hypogonadism comprising measurement of serum testosterone, a sex steroid, in addition to prolactin, FSH, and LH levels, as compared to normal ranges [see p.54, right column, paragraph 2] (claim 20). It would have been obvious to a person of ordinary skill in the art seeking to treat TBI patients with hypogonadism to combine the teachings of Zygun and Lee et al. with the diagnostic method of Carnegie to identify individuals that are not capable of normal gonadal hormone synthesis and secretion and administer hCG and testosterone according to a known and routine administration timeline.
Therefore, claims 1, 6-9, 11, and 15-20 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
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/T.D.J./Examiner, Art Unit 1675
/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675