Detailed Action
The present office action is in response to the amendments filed on 26 Nov 2025.
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 9-19 of the pending application have been examined on the merits. Acknowledgement is made of the amendments filed 26 Nov 2025. Acknowledgement is made of the cancellation of claims 1-8.
Priority
Applicants identify the instant application, Serial #: 17/798,143, filed 08 Aug 2022, as a National Stage Entry of International Patent Application #: PCT/TR2021/050115, filed 10 Feb 2021, which claims foreign priority from Foreign Application #: TR2020/01995, filed 10 Feb 2020.
Response to Applicant Arguments
Acknowledgement is made of the amendments filed 26 Nov 2025.
The rejection of claims 9-16 under 35 U.S.C. § 101 is rendered moot following applicant amendments.
The rejection of claims 9-16 under 35 U.S.C. § 112(b) is rendered moot following applicant amendments.
The rejection of claims 9-16 under 35 U.S.C. § 112(a) is rendered moot following applicant amendments. A new grounds of rejection for claims 9-19 under 35 U.S.C. § 112(a) has been made. This rejection is necessitated by applicant amendments.
Regarding the rejection of claims 9-16 under 35 U.S.C. § 102(a)(1) as being anticipated by Alici-Garipcan et al. (bioRxiv, 2019, 1-11; provided in IDS 07/03/24), applicant has provided a declaration to show Alici-Garipcan et al. is not prior art and is excepted under 35 U.S.C. § 102(b)(1)(A). However, applicant has not submitted a certified English translation of the foreign priority application with the statement of accuracy and the effective filing date has not been perfected. The rejection has not been overcome and is restated below.
Regarding the rejection of claims 9-11 and 13 under 35 U.S.C. § 102(a)(1) as being anticipated by Rai et al. (J Turkish-German Gynecol Assoc, 2012, 13:284-286; provided in the office action mailed 28 May 2025), hereinafter Rai, in light of Simonds et al. (Ped Rheumatol, 2024, 22:6; provided in the office action mailed 28 May 2025, cited for evidentiary purposes), hereinafter Simonds, applicant arguments have been fully considered but are not persuasive.
In the reply filed 26 Nov 2025, applicant argues that while Rai teaches the treatment of familial recurrent hydatidiform mole using methotrexate, it does not teach, suggest, or relate the treatment to BMP receptor inhibition, nor does it provide any indication that methotrexate is administered for the purpose of modulating BMP signaling (pgs. 7-8). Applicant further argues that Simonds reports observations in an unrelated cell type as the instant claims and does not identify methotrexate as a BMP receptor inhibitor (pg. 8).
This is not persuasive. MPEP § 2131.01(III) states, "that as long as there is evidence of record establishing inherency, failure of those skilled in the art to contemporaneously recognize an inherent property, function or ingredient of a prior art reference does not preclude a finding of anticipation." Further, MPEP § 2112(II) states there, "is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference." Rai does not recognize that methotrexate is a BMP inhibitor, but this inherent characteristic is evidenced by Simonds. Simonds teaches methotrexate is a BMP4 inhibitor (Title; pg. 1, Conclusions; pg. 3, column 1; pg. 5, column 1; pg. 5, column 2; pg. 6, column 2; and pg. 7, column 1).
In light of the discussion above, the rejection of claims 9-11 and 13 under 35 U.S.C. § 102(a)(1), as anticipated over Rai in light of Simonds is maintained for the reasons of record and restated below.
Claim Rejections - 35 USC § 112(a)
Claims 9-19 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 the treatment of molar pregnancies by administering a BMP receptor inhibitor, does not reasonably provide enablement for prevention of molar pregnancies in a genetically predisposed subject by administering a BMP inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
the quantity of experimentation necessary,
the amount of direction or guidance provided,
the presence or absence of working examples,
the nature of the invention,
the state of the prior art,
the relative skill of those in the art,
the predictability of the art, and
the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention and breadth of the claims
The nature of the invention is a method of treating a molar pregnancy in a subject or preventing a molar pregnancy in a genetically predisposed subject by administering a BMP4 inhibitor based on the principles that BMP proteins are implicated in the differentiation and proliferation of trophoblasts and molar pregnancy is a disease which is caused by uncontrolled growth and proliferation of trophoblasts. The claims are broad and claim the prevention and treatment of molar pregnancies by administering a BMP receptor inhibitor.
The state of the prior art and predictability of the art
The following references are pertinent to showing the state of the art in treating molar pregnancies and speak to the predictability of preventing molar pregnancies: Darling et al. (Curr Obstet Gynecol, 2022, 11:133-141; provided in the office action mailed 28 May 2025, cited for evidentiary purposes), hereinafter Darling, Hui et al. (Annu Rev Pathol Mech Dis, 2017, 12:449-485; provided in the office action mailed 28 May 2025, cited for evidentiary purposes), hereinafter Hui, Soper (Obstet Gynecol, 2021, 137:355-370; cited for evidentiary purposes), hereinafter Soper, and Simonds (cited for evidentiary purposes).
Darling, cited for evidence, teaches the true incidence of molar pregnancy is difficult to assess given the rarity of this disease and that unrecognized molar pregnancies may present very early and be indistinguishable from spontaneous abortion (pg. 134, column 1). Darling further teaches that in families with recurrent molar pregnancy, genetic links have been identified, particularly including mutations in NLRP7 and KHDC3L genes (pg. 134, column 2). Darling further teaches that data regarding risk factors such as diet, smoking status, oral contraceptive use, and blood type have been largely inconsistent (pg. 135, column 1). Darling teaches that hydatidiform moles are rare and caused by abnormal fertilization events (pg. 138, column 2). Darling also teaches that initial treatment of molar pregnancy begins with uterine evacuation to remove the genetically abnormal tissue (pg. 137, column 1). Darling teaches that hysterectomy is an alternative management strategy (pg. 137, column 1). Darling teaches that another option for treatment is prophylactic chemotherapy to reduce the risk of malignant transformation of the mole (pg. 137, column 1). Darling thus speaks to the lack of ability to determine who is at risk for hydatidiform moles, and the fact that this is a rare event makes it all the more difficult to predict and prevent these abnormal fertilization events. Darling also is useful for teaching the state of the art for treatment of hydatidiform moles is surgical in nature, and only looks towards chemotherapy for a treatment option with no comment on hydatidiform mole prevention.
Hui, cited for evidence, teaches that both NLRP7 mutations and KHDC3L mutations are genes linked to familial biparental complete hydatidiform moles and that KHDC3L mutations are responsible for 10-14% of all cases of familial biparental complete hydatidiform moles (pg. 453-454). Hui further teaches that not all NLRP7 mutations affect trophoblastic proliferation and embryonic development in the same fashion, highlighting unpredictability in the art concerning those who are genetically predisposed for molar pregnancies.
Soper, cited for evidence, teaches that germline mutations in NLRP7 and KHDC3L are observed in 48–80% and 10–14% of patients with repetitive moles, respectively (pg. 356, column 2). Soper teaches that hCG assays and increased use of routine early ultrasound evaluations in pregnancy this leads to frequent diagnosis in early pregnancy but that women with consecutive molar pregnancies should undergo genetic testing for mutations in NLRP7 and KHDC3L and assisted reproduction techniques are recommended for future pregnancies if mutations are identified (pg. 357, column 1; pg. 359, column 2). Soper also speaks to the use of prophylactic therapy to prevent hydatidiform moles, teaching that methotrexate (which is a BMP4 inhibitor as evidenced by Simonds (Title; pg. 1, Conclusions; pg. 3, column 1; pg. 5, column 1; pg. 5, column 2; pg. 6, column 2; and pg. 7, column 1)), regimens reduced incidence of postmolar gestational trophoblastic neoplasia in women after molar evacuation compared with those who did not receive chemotherapy but that that there are anecdotal cases of fatalities caused by prophylactic chemotherapy (pg. 360, column 1). Soper teaches that prophylactic chemotherapy is usually not recommended unless a patient has high-risk features (pg. 360, column 1).
While diagnoses and treatment of hydatidiform moles is well documented in the art, prevention of hydatidiform moles is unpredictable due to the lack of known risk factors, rarity of the condition, multiple markers of genetic predisposition for molar pregnancies, and prophylactic treatments for molar pregnancies not being recommended in the majority of cases without further guidance from the instant specification to guide a person of ordinary skill in the art.
Presence of working examples and amount of guidance provided
Applicant provides examples detailing the differences between cellular models of healthy cells and hydatidiform moles. There is further experimental evidence provided which shows the introduction of BMP4 inhibitors decrease the trophoblast differentiation in hydatidiform mole models. Given the unpredictability in the art for the prevention of hydatidiform moles, the specification would need to provide guidance and examples for the person having ordinary skill in the art to understand how BMP4 inhibitors prevent hydatidiform moles. However, there is no guidance or examples provided that would teach the artisan how to use BMP inhibitors to prevent hydatidiform moles.
The artisan is thus left questioning how to identify those at risk for hydatidiform moles and how BMP4 inhibitors prevent the formation of hydatidiform moles.
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.
Claim(s) 9-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alici-Garipcan et al. (bioRxiv, 2019, 1-11; provided in IDS 07/03/24), hereinafter Garipcan.
The instant claims are directed to the use of a BMP inhibitor to treat molar pregnancies (instant claim 9). Further limitations include type of molar pregnancy (instant claims 10-11), the molar pregnancy being caused by a mutation in the NLRP7 gene (instant claim 12), and the type of BMP inhibitor (instant claims 13-16).
Garipcan teaches the derivation of iPSCs from a patient with a recurrent hydatidiform mole diagnosis (pg. 1, column 2). Garipcan further teaches the iPSCs had a mutation of NLRP7 in the hydatidiform mole pathology (pg. 1, column 2). Garipcan teaches treating the hydatidiform mole models with the BMP4 inhibitor LDN193189 impeded the differentiation of hydatidiform mole cells (pg. 6, column 1). Garipcan teaches that the results show that NLRP7 deficient iPSCs can model complete hydatidiform moles and that BMP pathway inhibition ameliorates trophoblast differentiation which can pave the way to therapeutic treatments for hydatidiform mole patients (pg. 6, column 2). Garipcan thus anticipates the instant invention of treating familial recurrent hydatidiform moles with NLRP7 mutations using the BMP4 inhibitor LDN193189.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim(s) 9-11 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rai, in light of Simonds.
The instant claims are directed to the use of a BMP inhibitor to treat molar pregnancies (instant claim 9). Further limitations include type of molar pregnancy (instant claims 10-11) and the type of BMP inhibitor (instant claim 13).
Rai teaches a patient with 5 complete hydatidiform moles (pg. 284, column 2). Rai further teaches the patient was diagnosed with familial recurrent hydatidiform moles (Abstract and pg. 285, column 1). Rai teaches the patient received methotrexate with folinic acid rescue to treat the residual disease (pg. 284, column 2). Simonds, cited for evidence, teaches methotrexate is a BMP4 inhibitor (pg. 1, Conclusions and pg. 5, column 2). Therefore, by treating a patient with familial recurrent hydatidiform moles using methotrexate, Rai inherently teaches treating familial recurrent hydatidiform moles using a BMP4 inhibitor.
Conclusion
No claim is 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625