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
Claims 1, 3, 6, 9, 12-14, 16-19, and 28-36 are pending. Claims 28-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species. Therefore, Claims 1, 3, 6, 9, 12-14, and 16-19 are presented for examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 12/08/2025 has been entered.
Election/Restrictions
Applicant elected 2-aminophenol sulfate with traverse in the reply filed on 9/27/2024.
Claim Rejections - 35 USC § 112 – Indefiniteness
New rejection
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, 6, 9, 12-14, and 16-19 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 method for
promoting healthy growth or angiogenesis in an unborn baby, promoting placental development, or inhibiting development of preeclampsia or fetal growth restriction (FGR) in a maternal subject, or
promoting healthy growth or angiogenesis in an unborn baby or inhibiting development of preeclampsia or fetal growth restriction (FGR) after implantation in a female subject that is fertile, ovulating, or seeking to implant an embryo,
by administering to a subject a composition comprising a compound.”
The claim is unclear because it recites multiple different biological outcomes including promoting healthy growth in an unborn baby, promoting angiogenesis in an unborn baby, promoting placental development, inhibiting development of preeclampsia, and inhibiting fetal growth restriction in a maternal subject. These outcomes correspond to different biological conditions affecting different physiological systems and patients (e.g., fetus vs. mother). The claim does not clearly specify which condition is being treated by the claimed method. Additionally, the claim recites administering the composition “to a subject” but it is unclear whether the subject refers to the maternal subject, the female subject, or the unborn baby.
Furthermore, the claim recites two alternative method descriptions in parts (i) and (ii). However, these alternatives overlap in scope because a “maternal subject” would inherently be a female subject after implantation. Thus, the boundaries between the two alternatives are unclear; thus, the claims do not clearly distinguish the separate claim scope.
The term “promoting healthy growth” in claim line 1 is a relative term which renders the claim indefinite. The term “healthy” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim does not specify what constitutes "healthy growth", how such growth would be measured, or relative to what baseline the growth this evaluated. One of ordinary skill in the art (POSA) is not apprised of the metes and bounds of the claimed invention.
Accordingly, a POSA would not be able to determine when the claim limitation is met.
For prior art purposes, the claim will be construed to mean that all treatment outcomes are achieved by administering the recited compound to a mother or female seeking to become pregnant, wherein any beneficial effect on the mother or infant resulting from said administration would promotes the health of the unborn baby.
Claim Rejections - 35 USC § 103
Rejection maintained, modified to address amendment
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.
Claims 1, 3, 6, 9, 12-14, and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Elinav et al. (US PG-PUB 2021/0353611 A1 – effective filing date 9/20/2018) in view of Kawamichi et al. (“Riluzole Use During Pregnancy in a Patient with Amyotrophic Lateral Sclerosis: a Case Report.” The Journal of International Medical Research 2010; 38: 720 – 726).
Claimed invention
Claim 1 is drawn to a method for
promoting healthy growth or angiogenesis in an unborn baby, promoting placental development, or inhibiting development of preeclampsia or fetal growth restriction (FGR) in a maternal subject, or
promoting healthy growth or angiogenesis in an unborn baby or inhibiting development of preeclampsia or fetal growth restriction (FGR) after implantation in a female subject that is fertile, ovulating, or seeking to implant an embryo
comprising administering to the subject a composition comprising:
a compound selected from, inter alia, 2-aminophenol sulfate (elected).
Prior art
Elinav teaches the administration of a pharmaceutical composition containing an effective amount of 2-aminophenol sulfate (2-APS) for treating amyotrophic lateral sclerosis (ALS). See Claim 21; see also 0132-0133.
While Elinav teaches administering 2-APS to a subject with ALS, Elinav does not expressly teach promoting healthy growth or angiogenesis in an unborn baby, promoting placental development, or inhibiting development of preeclampsia or fetal growth restriction (FGR) in a maternal subject.
However, it was already known that ALS, a relentlessly progressive neurological disorder, is a deadly disease that is dangerous for pregnant ALS patients – so much so that even if the effects of an ALS drug on maternal or fetal health is unknown, one may still decide to administer the ALS drug during pregnancy, i.e., gestation, to continue to treat the disorder. For example, Kawamichi teaches that those with ALS have a median survival of 3–5 years. Respiratory paralysis in ALS patients leads to death and the disorder is dangerous with pregnancy. Kawamichi teaches ALS medication administration prior to and throughout pregnancy even though adverse effects on maternal and fetal health were unknown.
Pregnancy with amyotrophic lateral sclerosis (ALS) is rare and generally considered dangerous. Riluzole is the only drug approved for use in ALS, but the effect on maternal and fetal health is unknown. We describe the case of an ALS patient taking riluzole throughout pregnancy. A 34-year old Japanese woman, who had been diagnosed with probable ALS 4 years earlier, visited our hospital for abdominal distension, without knowing that she was pregnant. The patient had been taking riluzole for 2 years, inclusive of her gestational months, and we decided to continue administration of the medication. The patient delivered a normal female infant transvaginally at 38 weeks gestation. The patient’s neurological status was stable1 year after delivery and the baby had developed normally. We found that, in this case, riluzole did not cause any side-effects to the pregnant woman or her fetus.
See abstract.
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease of the upper and lower motor neurons, causing irreversible muscle weakness and atrophy. The illness is relentlessly progressive, leading to death from respiratory paralysis, with a median survival of 3–5 years. In the USA and Europe, males are somewhat more frequently affected than females, and the disease does not usually occur until after 50 years of age. Some cases of ALS presented before or during pregnancy have been described. The only drug that is licensed for the treatment of ALS is riluzole, which was approved in 1996 because it modestly lengthens survival, but there has been no report on its use during pregnancy.
See Kawamichi, p. 720.
Thus, Kawamichi makes clear – given the negative prognosis and danger of ALS in pregnancy –if a drug is known to provide therapeutic benefits to ALS patients, one may decide to treat or continue to treat ALS in a person by administering a beneficial therapeutic even after she becomes pregnant.
A person of ordinary skill in the art (POSA) would have found it obvious to administer (or continue to administer) a composition containing an effective amount of 2-aminophenol sulfate (2-APS) to an amyotrophic lateral sclerosis (ALS) patient for treating ALS in a patient who becomes pregnant (i.e., administration prior to and throughout her pregnancy) because Elinav teaches 2-APS is effective for treatment of ALS and Kawamichi teaches continued administration of an ALS medication prior to and during pregnancy to avoid disease progression, even without prior knowledge of potential detrimental effects on the mother or fetus.
The POSA would have reasonably believed that 2-APS would remain useful for treating ALS in a pregnant woman afflicted with this disease because 2-APS administration was already known to be effective for treating ALS in humans.
Accordingly, the POSA would have reasonably expected that the known ALS therapeutic efficacy of 2-APS would continue during pregnancy when administered to maintain treatment of the maternal subject. The POSA would have no reason to believe that 2-APS administration should be terminated solely due to pregnancy, especially given the established need to maintain ALS treatment during pregnancy. The claimed beneficial outcomes resulting from administration of the compound – wherein the method of administering 2-aminophenol sulfate to a pregnant woman with ALS results in: promotion of healthy growth or angiogenesis in an unborn baby, promotion of placental development, or inhibition of development of preeclampsia or fetal growth restriction (FGR) – would have been obvious.
In this case, the prior art suggests the same method of administration of 2-aminophenol sulfate to pregnant women prior to and throughout her pregnancy. The POSA would have reasonably understood that maintaining effective treatment of a serious maternal disease supports maternal health during pregnancy. Maintaining maternal health during pregnancy would reasonably be expected to promote healthy fetal viability, growth and development.
Therefore, the claimed beneficial outcomes achieved by the recited compound administration – such as promoting healthy growth or angiogenesis in an unborn baby, promoting placental development, or inhibiting development of preeclampsia or fetal growth restriction (FGR) – would have been obvious consequences of administering 2-APS to a pregnant ALS patient as taught by the prior art.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 3 limits claim 1, wherein promoting healthy growth comprises promoting an increase in one or more of fetal weight, fetal volume, fetal surface area, fetal brain volume, fetal ventricle volume, and fetal brain: body ratio. Claim 6 limits claim 1, wherein promoting placental development comprises promoting an increase in one or more of a placental angiogenesis, placental immunity, and placental weight. Claim 9 limits claim 1, wherein promoting angiogenesis in the unborn fetus comprises promoting development of uterine natural killer (uNK) cells. However, these limitations merely describe results or biological mechanisms associated with the administration of the compound and do not require and additional method step beyond administering the composition. Accordingly, these limitations do not patentably distinguish the claimed method from the prior art method of administering the compound as discussed above. As indicated above, in this case, the prior art suggest the same method of administration of a substantially identical composition comprising 2-aminophenol sulfate to pregnant women prior to and throughout her pregnancy. Therefore, the benefits that method promotes healthy growth or angiogenesis in an unborn baby, promotes placental development, or inhibits development of preeclampsia or fetal growth restriction (FGR), would have been obvious.
Claim 12 limits claim 1, wherein the subject is characterized by a depleted maternal microbiome. Claim 13 limits claim 12, wherein the subject is germ-free (GF) or antibiotic-treated (ABX) prior to administration of the composition. Elinav teaches prior to administration, the subject may be pretreated with an agent which reduces the number of naturally occurring microbes in the microbiome. See Elinav, 0172.
Claim 14 limits claim 1, wherein the subject is a mammal. Claim 15 limits claim 14, wherein the mammal is a human. Elinav concerns the treatment of humans. See 0100.
Claim 16 limits claim 15, wherein the composition is administered during the first trimester of gestation. Claim 17 limits claim 16, wherein the composition is administered during the second trimester of gestation. Claim 18 limits claim 15, wherein the composition is administered during the third trimester of gestation. Claim 19 limits claim 15, further comprising administering the composition to the subject prior to gestation. As outlined above, Kawamichi teaches ALS medication may be administered prior to and continued throughout pregnancy. See Kawamichi, abstract. Thus, the POSA would have found it obvious to treat ALS in a female subject prior to and throughout her pregnancy.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive. Applicant argues that Elinav fails to teach administration of 2-APS for promoting healthy growth, angiogenesis, placental development, or inhibiting preeclampsia or FGR as recited in Claim 1. However, the rejection does not rely on Elinav to disclose these outcomes. Elinav teaches administration of 2-APS to human subjects for treating ALS. Kawamichi teaches that ALS medications may be administered prior to and throughout pregnancy in ALS patients despite uncertainty regarding fetal effects. The rejection relies on the combined teachings of Elinav and Kawamichi for the method of administering an ALS therapeutic to a female subject who becomes pregnant. The claimed outcomes relating to fetal growth, angiogenesis, placental development, preeclampsia or FGR constitutes intended results of administering the claimed composition to the recited patient population. The claims do not require any step that actively induces these effects beyond administration of the compound. Therefore, the recitation of results does not render the claimed method nonobvious.
Applicant further argues that Elinav teaches away from administration to a pregnant woman or fertility-seeking females because Elinav does not include this particular population of subjects. Applicant states that the criteria for selecting subjects excluded pregnant women. Applicant suggests concerns for medication safety to mother and fetus in pregnancy and further states that Kawamichi concerns riluzole as the ALS-treating agent which is distinct from the claimed 2-aminophenol sulfate. While Elinav excluded pregnant/fertility-treatment subjects from participating in the study, it nevertheless teaches that 2-aminophenol sulfate is safe and effective in human subjects, including treatment of ALS. Although Kawamichi may not teach the claimed compound, the reference teaches the deep concern with ALS in pregnancy and confirms continued pharmacological treatment of ALS during pregnancy without adverse effects to the fetus even though the potential adverse effects against the mother or fetus were unknown. This would oppose the assertion that a POSA would avoid treating a pregnant subject with ALS using 2-aminophenol sulfate due to an overwhelming concern for potential pharmacological safety issues as compared to the well-established danger posed by ALS during pregnancy. The POSA would rather reasonably expect that a compound taught to possess pharmacological efficacy against ALS such as 2-aminophenol sulfate could likewise continue to be administered to women to treat ALS who become pregnant or seek fertility. Furthermore, the weighing of the benefit versus risk factors in treating diseases or conditions in a risk/benefit analysis has been well established in medicine.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the rejection is base on the explicit teachings of Elinav, which discloses administration of 2-APS for treating ALS, and Kawamichi, which teaches continuation of ALS therapy during pregnancy. The combination merely applies the known therapeutic compound taught by Elinav in the context of pregnancy described by Kawamichi.
The potential for maternal/fetal toxicity or teratogenic effects does not, in itself, render administration of a therapeutic agent during pregnancy nonobvious. The use of medication with known or suspected risks is a well-established aspect of medical practice when treating serious maternal conditions. For example, mood stabilizers such as lamotrigine and carbamazepine are routinely used to manage bipolar disorder in pregnant women, despite recognized concerns regarding fetal safety. Clearly, in such cases, treatment decisions are guided by a risk-benefit analysis that prioritizes stabilization of the mother’s condition when the untreated disease poses risks to the mother and baby. (See Tillery et al. "Oh baby! A review of mood stabilizers for bipolar disorder in the child-bearing woman." Mental Health Clinician 3.2 (2013): 61-70 - particularly abstract; Table 3 at page 63 and the text at page 64.) Similarly, in the context of ALS – a rapidly progressive and often fatal disorder with known dangers in pregnancy – the POSA would have understood that continuation of an effective therapeutic like 2-APS during pregnancy could be justified despite theoretical fetal risks.
Further regarding Applicant’s arguments that the claimed benefits (e.g., fetal development, inhibition of FGR, preeclampsia, etc.) are not disclosed or suggested by the prior art. However, there is no evidence that the claimed benefits are unexpected results of 2-aminophenol sulfate administration to the pregnant/fertile/ovulating/pregnancy-seeking patient. The assertion of benefits in the claim language are not sufficient to overcome a prima facie case of obvious.
It would have been obvious to combine the teachings of Elinav and Kawamichi because both teach administration of ALS medication in human subjects and at least one discloses administration during pregnancy. The claimed administration of 2-aminophenol sulfate to achieve maternal and fetal benefits would have been within the routine skill of the art in view of the combined teachings of Elinav and Kawamichi. Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622