DETAILED ACTION
Applicant’s response, filed 01/16/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 01 February 2023 has been entered.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Status
Claims 17-31 are pending.
Claims 1-16 are canceled.
Claims 18, 20, and 31 are objected to.
Claims 17-31 are rejected.
Priority
The instant application claims the benefit of priority as a continuation in part of US application No. 16/503286, which claims the benefit of priority as a continuation of U.S. Application No. 14/772,554 filed 09/03/2015, which claims the benefit as a 371 filing of International Application No. PCT/US14/20223 filed 03/04/2013, which claims the benefit of priority to U.S. Provisional Application No. 61/772,054 filed 03/04/2013. The claims to the benefit of priority are acknowledged. As such, the effective filing date of claims 17-25, 27 and 30-31 is 03/04/2013 and as estrogen is not introduced until 16/503286, the effective filing date of claims 26 and 28-29 is 07/03/2019.
Drawings
The Drawings submitted 10/08/21 and replacement sheets submitted on 3/21/2022 are accepted.
Claim Rejections- 35 USC § 112
The outstanding rejection to the claims is maintained
35 USC § 112(b)
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.
Claims 17-31 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 17 recites “the lower limit of a normal free sex steroid concentration from a healthy individual” is a variable quantity, so a POSITA has no way of knowing whether the patient’s limit is below the normal limit. Also, it is not known where the concentration is coming from, please clarify from where the concentration is obtained. Claim(s) 8-27 is/are rejected for the same reason because they depend from claim 17, and does not resolve the indefiniteness issue in those claims. Claims 28 and 30 have the same indefinite issue as claim 17 with different objectives. Claim(s) 29 and 31 is/are rejected for the same reason because they depend from claims 28 and 30, and does not resolve the indefiniteness issue in those claims.
Response
Applicant submits person of ordinary skill in the art would understand from the teaching of the specification and the general knowledge in the art what a concentration of free sex steroid would be from a healthy individual, and so would understand what the lower limit [p. 8, par. 2].
It is respectfully found not persuasive. As described by the applicants response and the specification describes how to measure free sex steroid concentration from an individual and provides non-limiting examples for the lower limit of free sex steroid concentration. The specification discloses the lower limit of a normal free sex hormone concentration from a healthy individual (e.g., in one embodiment, the lower limit of testosterone is 114.6 pg/ml) [0012]. The specification further discloses one of skill in the art understands that the lower limit of a normal free testosterone concentration will vary according to assay used to detect total testosterone, SHBG, and albumin and will vary in a different patient populations [0077]. Thus the lower limit used for implementation should correspond to the lower limit obtained in a healthy individual using the same assays as used on the biological sample from the test individual, and the lower limit used should be the lower limit from a healthy individual of the same age and type of the test individual [0077]. As the lower limit can vary based on the above mentioned reasons, to overcome the 112(b) rejection applicant could for recite what the lower limit is or for example provide an active step on how it is calculated or measured showing how to establish a lower limit by measuring a sex steroid of a healthy individual and a patient and comparing the two to determine whether the patient is lower than the healthy individual into the claim language or recite what the lower limit is.
Claim Rejections - 35 USC § 102
The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein. The amended claims have added an additional step of identifying a patient with a sex steroid disorder.
Double Patenting
The nonstatutory double patenting rejection with US Application 16503286 is maintained.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 17-31 are rejected on the ground of nonstatutory double patenting as being anticipated by claims 23-31and 33-39, of U.S. Application No. 16503286, (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim methods and systems for the diagnosis and treatment of sex hormone disorders.
Instant Application
U.S. Application 16503286
Claims
Limitations
Claims
Limitations
17
A method of identifying and treating a patient having a sex steroid disorder comprising identifying a patient having a free sex steroid concentration that is below the lower limit of a normal free sex steroid concentration from a healthy individual, based on:
23
A method of diagnosing and treating a sex steroid disorder in a patient comprising the following steps:a) obtaining a biological sample from the patient;b) measuring in the biological sample obtained in step a, and ;d) diagnosing the patient with a sex steroid disorder when the free sex steroid concentration determined in step c) is below the lower limit of a normal free sex steroid concentration from a healthy individual; ande) when the patient is diagnosed with a sex steroid disorder in step d), administering an effective amount of sex steroid, sex steroid derivatives, and/or analogues thereof in step d), thereby treating the sex steroid disorder.
i
i) total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
23
i) a total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
ii
ii) total concentration of the sex steroid,
23
ii) a total concentration of sex steroid
iii
iii) concentration of albumin; and wherein the free sex steroid concentration is calculated by an implementation of an ensemble allostery model representing the binding equilibria (i) between the sex steroid and the first monomer of the SHBG and between the sex steroid and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first sex steroid molecule with a different affinity, and (ii) between the sex steroid and the albumin, and administering an effective amount of sex steroid, sex steroid derivatives, and/or analogues thereof to the patient.
23
iii) a concentration of albumin;c) determining the concentration of free sex steroid in the biological sample based on (i)-(iii) measured in step b), using an implementation of an ensemble allostery model representing the binding equilibria (i) between the sex steroid and the first monomer of the SHBG and between the sex steriod and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first sex steroid molecule with a different affinity, and (ii) between sex steroid and the albumin
18
wherein the sex steroid is selected from the group consisting of a testosterone steroid, an estradiol steroid, and estrone steroid, and a dihydrotestosterone steroid.
24
wherein the sex steroid is selected from the group consisting of a testosterone steroid, an estradiol steroid, an estrone steroid, and a dihydrotestosterone steroid.
19
wherein the identification of the patient's free sex steroid concentration is further based on:iv) A concentration of at least one non-testosterone steroid.
25
wherein the step of measuring in the biological sample further comprises measuring in the biological sample iv. A concentration of at least one non-testosterone steroid.
20
wherein the non-testosterone steroid is selected from the group consisting of an estradiol steroid, an estrone steroid, and a dihydrotestosterone steroid.
26
wherein the non-testosterone steroid is selected from the group consisting of an estradiol steroid, an estrone steroid, and a dihydrotestosterone steroid.
21
wherein the identification of the patient's free sex steroid concentration is further based on:iv) a concentration of at least a second sex steroid, wherein the second sex steroid is different than the sex steroid in (ii).
27
wherein the step of measuring in the biological sample further comprises measuring in the biological sample:iv) a concentration of at least a second sex steroid, wherein the second sex steroid is different than the sex steroid that was measured in step (b).
22
wherein the identification of the patient's free sex steroid concentration is further based on the concentration of the second sex steroid in a biological sample from the patient using an implementation of the ensemble allostery model comprising readjusting a second equilibria between the microstates upon binding of the second sex steroid molecule to the first monomer and the allosteric interaction between two monomers of the SHBG.
34
wherein the method further comprises the step of determining the concentration of the second sex steroid in the biological sample using an implementation of the ensemble allostery model comprising readjusting a second equilibria between the microstates upon binding of the second sex steroid molecule to the first monomer and the allosteric interaction between two monomers of the SHBG.
23
wherein the patient's free sex steroid concentration is further determined based on:iv) the concentration of one or more analytes.
28
wherein the step of measuring in the biological sample further comprises measuring in the biological sample:iv) the concentration of one or more analytes.
24
wherein the patient's free sex steroid concentration is further based on measuring one or more of the concentrations in the biological sample using at least one analytical method.
29
wherein the step of measuring in the biological sample further comprises measuring one or more of the concentrations in the biological sample using at least one analytical method.
25
wherein the at least one analytical method is selected from the group consisting of an immunoassay and a mass spectrometry-based assay.
30
, wherein the at least one analytical method is selected from the group consisting of an immunoassay and a mass spectrometry-based assay.
26
wherein the sex steroid disorder comprises an estrogen deficiency.
31
wherein the sex steroid disorder comprises an estrogen deficiency.
27
wherein the effective amount of administrated sex steroid, sex steroid derivatives, and/or analogues thereof is adjusted for treatment of the sex steroid disorder based on the determined free sex steroid concentration.
33
adjusting the dose of administered sex steroid, sex steroid derivatives, and/or analogues thereof for treatment of the sex steroid disorder
28
A method of identifying and treating a patient having a sex steroid disorder comprising an estrogen excess, comprising identifying a patient having an estrogen excess that is above the upper limit of a normal free sex steroid concentration from a healthy individual, based on:
37
A method of treating a patient identified to have a sex steroid disorder in a patient comprising administering an effective amount of sex steroid, sex steroid derivatives, and/or analogues thereof to the patient determined to have a wherein the patient's free sex steroid concentration that is below the lower limit of a normal free sex steroid concentration from a healthy individual, wherein the patient's free sex steroid concentration is determined based on
i
i) total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
37
a total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
ii
ii) total concentration of the sex steroid,
37
a total concentration of testosterone
iii
iii) concentration of albumin; and wherein the free sex steroid concentration is calculated by an implementation of an ensemble allostery model representing the binding equilibria (i) between the sex steroid and the first monomer of the SHBG and between the sex steroid and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first sex steroid molecule with a different affinity, and (ii) between the sex steroid and the albumin and reducing the amount of estrogen in the patient.
37 and 39
using an ensemble allostery model representing the binding equilibria (i) between testosterone and the first monomer of the SHBG and between testosterone and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates S2 and S'2, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first testosterone molecule with a different affinity
wherein the reducing the amount of estrogen in the patient further comprises adjusting the dose of administered sex steroid, sex steroid derivatives, and/or analogues thereof.
29
wherein the reducing the amount of estrogen in the patient further comprises adjusting a dose of administered sex steroid, sex steroid derivatives, and/or analogues thereof.
39
wherein the reducing the amount of estrogen in the patient further comprises adjusting the dose of administered sex steroid, sex steroid derivatives, and/or analogues thereof.
30
A method of monitoring and optimizing treatment of a patient being treated for having a sex steroid disorder comprising monitoring the patient being treated for having a sex steroid disorder by identifying a free sex steroid concentration that is above or below the free sex steroid concentration of the patient prior to being treated for having the sex steroid disorder, based o
35
A method of monitoring and optimizing treatment for a sex steroid deficiency in a patient comprising the following steps:a) obtaining a biological sample from the patient who is on a treatment of the sex steroid deficiency;b) measuring in the biological sample obtained in step a)
i
i) total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
35
a total concentration of sex-hormone binding globulin ("SHBG"), which is a dimer having a first monomer and a second monomer,
ii
ii) total concentration of the sex steroid,
35
a total concentration of testosterone
iii
iii) concentration of albumin; and wherein the free sex steroid concentration is calculated by an implementation of an ensemble allostery model representing the binding equilibria (i) between the sex steroid and the first monomer of the SHBG and between the sex steroid and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first sex steroid molecule with a different affinity, and (ii) between the sex steroid and the albumin, and administering a modified amount of sex steroid, sex steroid derivatives, and/or analogues thereof to the patient.
35
using an ensemble allostery model representing the binding equilibria (i) between testosterone and the first monomer of the SHBG and between testosterone and the second monomer of the SHGB, wherein the unliganded SHBG has at least two distinct interconverting microstates S2 and S'2, and wherein the first monomer and the second monomer have an allosteric interaction such that each of the microstates binds a first testosterone molecule with a different affinity
31
wherein the sex steroid is selected from the group consisting of a testosterone steroid, an estradiol steroid, and estrone steroid, and a dihydrotestosterone steroid.
36
wherein the sex steroid is selected form the group consisting of a testosterone steroid, an estradiol steroid, and estrone steroid, and a dihydrotestosterone steroid.
Conclusion
No claims are allowed.
It is noted that claims 23, 35, and 37 are free from the prior art as the prior art does not teach or fairly suggest identifying at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer and calculating the free testosterone or sex steroid concentration in a biological sample using an ensemble allostery model encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule or sex steroid molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer in claim 1. The closest prior art is Boone (US 2010/0273275 A1; IDS Document) which discloses calculating the free and bioavailable steroid concentrations for androgen and estrogen steroids, including testosterone, estradiol and estrone, using the law of mass action mathematical model that utilizes the total steroid, SHBG and albumin concentrations as parameters (abstract; paras. [0011]-[0067]). Boone is silent to identifying at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer and calculating the free testosterone or sex steroid concentration in a biological sample using an ensemble allostery model encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule or sex steroid molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/D.M.B./Examiner, Art Unit 1685 /Soren Harward/Primary Examiner, TC 1600