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 Application/Amendments/Claims/RCE 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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 10/20/2025 has been considered.
Claims 20-24 are newly added. Claims 2 and 5 have been canceled. Claims 1, 3 and 7-24 are pending. Claims 7-15 are withdrawn from further consideration with traverse pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 3 and 16-24 are the subject of the present official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application EP18200408.5 and PCT/EP2019/077575 filed on 10/15/2028 and 10/11/2019, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 10/15/2018.
Withdrawn Rejections
The 35 U.S.C. 102(a)(1) rejections of claim 1 has been withdrawn in light of applicants claim amendments further defining that the endocervical stem cells are cultured in a Wnt proficient medium and the ectocervical stem cells are cultured in a Wnt deficient medium which comprises a cAMP pathway agonist.
The 35 U.S.C. 103 rejection of claims 1-3, 5 and 16-19 has been withdrawn and newly applied in modified form in light of applicants claim amendments which move the limitations from canceled claim 2 into independent claim 1.
The provisional nonstatutory double patenting rejection of claim 1 over claims 1-7 of co-pending Application No: 16/967,548 (US Patent Application Publication Number US 2021/0230555) has been withdrawn in light of applicants claim amendments further defining the culture medium.
New 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 1, 3, 16-22 and 24 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 pre-AIA the applicant regards as the invention. This rejection is newly applied to address applicants claim amendments on 10/20/2025.
Claims 1, 3, 16-22 and 24 describe a cervix epithelial cell organoid culture that can be stably propagated for a time of at least six months. See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when "things which may be done are not required to be done". Specifically, it is unclear whether the claimed composition or apparatus may be infringed if the recited limitation does not occur. In other words, can the claimed composition or apparatus be infringed if the epithelial cell organoid culture is not stably propagated for at least six months?
Claim Interpretation
Claim 1 describes cultivating cervix stem cells in a “cell culture medium” under conditions wherein a “cervix epithelial cell organoid culture” is formed. Taking the broadest reasonable interpretation, cell culture medium reads on ANY culture medium which leads to the conversion and propagation of cervix stem cells to a cervix epithelial cell organoid culture. Only in claims 3, 17-18, 20-22 and 24 are limitations introduced further defining the composition of the cell culture medium.
With respect to the cervical epithelial cell organoid cultures that “can be” stably propagating for at least six months, it is emphasized that there is no express requirement in claim 1 that the cervix epithelial cell organoid culture is actually stably propagated for at least six months, only that the organoid culture is “capable” of such. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure, see MPEP 2111.04.
Furthermore, cervix epithelial cell organoid culture is interpreted broadly given that the Examiner is unable to find an express definition in the specification or further structural characteristics described in the claims.
New 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 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.
Claims 1, 3 and 16-20, 22 and 24 are newly rejected under 35 U.S.C. 103 as being unpatentable over Villa et al. "Human Cervical Keratinocyte-Derived Monolayer and Organoid Cultures for Disease Modelling and Drug Screening." bioRxiv (2018): 373456 (hereinafter Villa, reference of record) as evidenced by Aden. The correlation of keratin expression with in-vitro epithelial cell line differentiation. Diss. 2009 (hereinafter Aden, reference of record) in view of Alhaque et al. "Three-dimensional cell culture: from evolution to revolution." Philosophical Transactions of the Royal Society B: Biological Sciences 373.1750 (2018): 20170216 (hereinafter Alhaque, reference of record) as evidenced by Martens et al. "Cytokeratin 17 and p63 are markers of the progenitor cell of the human uterine cervical epithelium, a putative HPV target cell." The Reserve Cell in the Uterine Cervix 24 (2004): 45 (hereinafter Martens, reference of record). This rejection is newly applied to address applicants claim amendments on 10/20/2025.
Claim 1: Villa describes a method for generating multi-layered cervical epithelial cell organoid cultures from cervical keratinocytes derived from cervical lesions tissue (Villa, abstract and pg 4, 11, 19). Villa describes methods for isolating and propagating cervical keratinocytes, wherein various sized biopsies were taken from cervical lesions and cultured in a suitable cell culture medium (Villa, phase 1: Methods for isolating and propagating cervical keratinocytes and Table 1). Importantly, Villa notes “differentiation was evident upon microscope examination”, indicating that undifferentiated cervix stem cells were also contained within the cervical lesions tissue biopsy (Villa, pg 11-12). This is further acknowledged in the discussion section wherein Villa states that stem cells which reside in the biopsies could be boosted in future experiments to increase culture yields (Villa, pg 20). To further support this argument, Aden is presented as an evidentiary reference showing that cervix stem cells which reside in the basal layer would be present in the tissue biopsy of Villa, thus reading on the limitations of claim 1 (Aden, pg 35; Fig 1.11 reproduced below).
With respect to human endocervical and ectocervical stem cells, it is argued that these would be encompassed in the cervical lesions tissue biopsies described by Villa. As evidence, Martens describes both human endocervical and ectocervical stem cells being present in the cervix basal membrane (Martens, pg 15). A generic disclosure will anticipate a claimed species covered by that disclosure when the species can be “at once envisaged” from the disclosure, such is the case presently, see MPEP § 2131.02.
Villa describes organoid culturing procedures and culturing medium conditions to form cervical epithelial cell organoid cultures are formed (Villa, pg 8-9 and Fig 2). With respect to the cervical epithelial cell organoid cultures that “can be” stably propagating for at least six months, it is emphasized that there is no express requirement in claim 1 that the cervix epithelial cell organoid culture is actually stably propagated for at least six months, only that the organoid culture is “capable” of such. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure, see MPEP 2111.04.
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Claims 3 and 20: In the discussion section, Villa describes future studies to boost stem cell culture yields and further propagate latent biopsy stem cells with specific medium formulations supplemented with factors such as Wnt (Villa, pg 20). Columnar endocervical epithelium cells which are positive for KRT7 and/or KRT8 are characteristic of human epithelial keratins and would be present in a cervical lesions tissue biopsy and consequently the cervical keratinocyte-derived organoids as evidenced by Aden (Aden, Table 1.4).
Claims 16 and 19: With respect to human endocervical and ectocervical stem cells, it is argued that these would be encompassed in the cervical lesions tissue biopsies described by Villa. As evidence, Martens describes both human endocervical and ectocervical stem cells being present in the cervix basal membrane (Martens, pg 15). A generic disclosure will anticipate a claimed species covered by that disclosure when the species can be “at once envisaged” from the disclosure, such is the case presently, see MPEP § 2131.02.
Villa does not expressly describe a cell culture medium that is Wnt proficient for culturing endocervical stem cells which are positive for markers KRT7 and/or KRT8 or cell culture medium that is Wnt deficient which contains a cAMP pathway agonist like forskolin for culturing ectocervical stem cells which are positive for the marker KRT5.
Claims 1, 17, 18, 22 and 24: Alhaque describes the culturing and applications of three-dimensional organoids for disease modeling (Alhaque, abstract). Alhaque describes the inclusion of cAMP pathway agonists like forskolin into organoid cultures, which was observed to promote swelling and promote proper organization of the organoid culture (Alhaque, 5. Disease modeling). With respect to squamous stratified ectocervical epithelial cells which are positive for the marker KRT5, it is argued that these cells are characteristic of human epithelial keratins and would be present in a cervical lesions tissue biopsy and consequently the cervical keratinocyte-derived organoids as evidenced by Aden (Aden, Table 1.4).
It would have been prima facie obvious to one of ordinary skill in the art to incorporate a cell culture medium that is Wnt deficient which contains a cAMP pathway agonist like forskolin as described by Alhaque in the methods for cervical epithelial cell organoid culture containing ectocervical stem cells as descried by Villa. It would have been a matter of combining prior art elements according to known methods to yield predictable results since forskolin is a known modulator of organoid development and morphology. The motivation for including cAMP pathway agonists like forskolin and not Wnt would be to modify the culturing conditions of the organoid to better resemble a disease state or morphology of interest. One of ordinary skill would have a reasonable expectation of success given that the inclusion of known culturing reagents is a routine part of cell culture development and is furthermore considered a result-effective variable. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1, 3 and 16-20, 22 and 24 to have been prima facie obvious to at the time the invention was made.
Claims 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Villa (supra), Aden (supra), Alhaque (supra), and Martens (supra) as applied to claims 1, 3 and 16-20, 22 and 24 above in further view of Boretto et al. "Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability." Development 144.10 (2017): 1775-1786 (hereinafter Boretto). This rejection is newly applied to address applicants claim amendments on 10/20/2025.
A description of Villa, Aden, Alhaque and Martens can be found above. The collection of cited art does not describe the activator of Wnt signaling as Wnt3a and/or RSPO1 or stably propagating the organoid culture for at least six months.
Claim 21: Boretto describes a long-term expandable organoid model from mouse and human endometrium tissue which is closely related to cervix epithelial tissue (Boretto, abstract and pg 1775). Boretto describes using an organoid culture medium supplemented with Wnt3a and RSPO1 conditioned media (25%v/v) (Boretto, pg 1775 and Fig 1). Boretto observed that high Wnt yielded cystic differentiated organoids while low Wnt yielded dense and less differentiated organoids (Boretto, pg 1778). Thus, Boretto shows that Wnt3a is an essential factor that controls stemness in the organoid cultures (Boretto, discussion).
Claim 23: Boretto describes the formation and expansion of organoids for more than 14 passages which were expanded for 5 months or more which is technically coextensive with at least six months (pg 1776, col 2).
It would have been prima facie obvious to one of ordinary skill in the art to use an activator of Wnt signaling like Wnt3a and/or RSPO1 as described by Boretto the methods for cervical epithelial cell organoid culture containing ectocervical stem cells as descried by Villa in view of Alhaque. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Wnt3a is a well-known Wnt signaling activator and has been shown to control stemness in closely related endometrium organoid cultures (Boretto, discussion). One would be motivated to select Wnt3a given its critical role in maintenance of the endocervical lineage and importance for long-term (+5 months) culture. One of ordinary skill would have a reasonable expectation of success given that the inclusion of known culturing reagents is a routine part of cell culture development and is furthermore considered a result-effective variable when controlling for endocervical lineage fate. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the instant claims to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634