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
Applicant’s response filed on 4/2/2026 has been considered. Claims 3 and 17 have been canceled. Claims 1 and 18 have been amended. 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 Claims 7-15 are withdrawn from further consideration with traverse pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking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, 16 and 18-24 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.
Claim Rejections - 35 USC § 112a, Written Description – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 16, 18-20 and 22-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement for introducing new matter and is supported by the disclosure 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 is a new rejection necessitated by amendment of the claims in the responses filed 4/2/2026. This is a New Matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Claim 1 has been amended to recite that the culture medium is a Wnt proficient medium comprising one or more activator of Wnt signaling pathway selected from the group consisting of Wnt3a and/or R-Spondin 1 (RSPO1) and “functionally equivalent Wnt pathway agonists”.
The Specification as filed only provides specific examples of Wnt pathway activators, with specific embodiments to Wnt3a and/or RSPO1.
“For the cultivation of endocervical organoids, e.g. human endocervical organoids a Wnt proficient medium is used, i.e. a medium comprising an activator of Wnt signaling such as Wnt3a and/or RSPO1.” (Spec, description of invention)
The genus of “functionally equivalent Wnt pathway agonists” refers to a specific genus that is not supported by the generic disclosure and specific examples of the instant specification. Functionally equivalent Wnt pathway agonists refer to a genus that is considered extraordinarily broad. It is thought to encompass any Wnt pathway activator including natural Wnt ligands like valproic acid, receptor antagonist blockers like RSPO1, monoclonal antibodies both known and yet to be discovered.
For each claim drawn to a genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in procession of the claimed genius. If a representative number of adequately descried species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
The instant specification provides no examples to support amending claim 1 to include any functionally equivalent Wnt pathway agonists. For example, the specification describes how specific Wnt pathway agonists like Wnt3a and RSPO1 act to control stemness cervical organoid cultures (Spec, section 2.2). Furthermore, the prior art does not support the breadth of applicants claim to any functionally equivalent Wnt pathway agonists. For examine, Boretto shows that Wnt3a in particular has been shown to control stemness in closely related endometrium organoid cultures for long-term (+5 months) culture and the unpredictability of these results (Boretto, discussion).
Thus, the instant specification not provide sufficient written description to support the claim to any functionally equivalent Wnt pathway agonists. Thus, is not clear that the Applicant was in possession of a genus of undefined Wnt pathway agonists which lead to culturing the claimed cervical organoids before the effective filing date of the claimed invention. This is a matter of written description, not a question of what one of skill in the art would or would not have known. “The trouble is that there is no disclosure, easy though it is to imagine it.” In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967); M.P.E.P. § 2163.05, part II. The material within the four corners of the as-filed specification must lead to the generic concept. If it does not, the material is new matter. Declarations and new references cannot demonstrate possession of a concept after the fact.
Maintained 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, 16 and 18-24 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 repeated for the same reasons as outlined in the Office Action mailed on 1/6/2026. A reply to applicant’s arguments is found below.
Claims 1, 16 and 18-24 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?
Response to Traversal
Applicant argues that the claims recite functional characteristics and capabilities of the claimed composition and should not render the claim indefinite, with reference to MPEP 2173.05g. Applicant argues that the limitation defines an intrinsic property of the claimed cervix epithelial cell organoid culture and a person of ordinary skill in the art would readily understand whether a given organoid culture meets this requirement.
This argument has been fully considered, but was not found persuasive since it is unclear whether the claimed composition or apparatus may be infringed if the recited limitation does not occur. The claims recite a functional limitation which may or may not occur, rendering the metes and bounds of the claim indefinite, see MPEP 2173.
Claim Interpretation
Applicants’ amendments describing a functionally equivalent Wnt pathway agonists broadly reads on factors such as Wnt.
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.
Maintained 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, 16, 18-20, 22 and 24 stand 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 repeated for the same reasons as outlined in the Office Action mailed on 1/6/2026. A reply to applicant’s arguments is found below.
Claims 1 and 20: 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.
With respect to Wnt signaling pathway selected from the group consisting of Wnt3a and/or R-Spondin 1 (RSPO1) and “functionally equivalent Wnt pathway agonists” as stated in the claim interpretation section, Applicants’ amendments describing a functionally equivalent Wnt pathway agonists broadly reads on factors such as Wnt. 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).
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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, 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, 16, 18-20, 22 and 24 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant points to the amendments to independent claim 1. Applicant argues that although Villa generally describes culture conditions for epithelial cell organoids, Villa does not disclose teh use of cervix stem cells of defined endocervical or ectocervical origin and the specific media requirements now recited in claim 1. Applicant traverses the rejection by arguing that Villa discloses cultivating differentiated cells in a specific keratinocyte medium. Applicant argues that Villa does not suggest cultivating cervix stem cells in a cell culture medium as described in amended claim 1.
This argument has been fully considered, but was not found persuasive since claim 1 describes cultivating cervix stem cells with a Wnt signaling pathway selected from the group consisting of Wnt3a and/or R-Spondin 1 (RSPO1) and “functionally equivalent Wnt pathway agonists”. As stated in the claim interpretation section, Applicants’ amendments describing a functionally equivalent Wnt pathway agonists broadly reads on factors such as Wnt. 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). Thus, 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.
Applicant further argues that Villa dies not disclose cultivating in a cell culture medium which is capable of stably propagating for at least six months. Applicant argues against Aden, which investigates the expression patterns of keratin markers such as K15 and K13 but does not describe cervix stem cells and does not suggest organoid cultures.
This argument has been fully considered, but was not found persuasive since one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145.The cervical lesions tissue biopsy used in the culturing procedures of Villa contains undifferentiated cervix stem cells (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). The disclosure of Aden was introduced to further support this wherein 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).
With respect to the cervical epithelial cell organoid cultures being capable of 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 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.
Claims 21 and 23 stand 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, 16, 18-20, 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 repeated for the same reasons as outlined in the Office Action mailed on 1/6/2026. A reply to applicant’s arguments is found below.
A description of Villa, Aden, Alhaque and Martens can be found above. The collection of cited art does not describe the specific 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.
Response to Traversal
Applicant argues that Boretto discloses organoids that are specifically directed to endometrial epithelial biology and are structurally and functionally distinct from cervix epithelial organoids as presently claimed. Applicant argues that the starting material is different and these lead to important differences in the derived cervix stem cell derived organoid systems. Applicant further argues that the culturing conditions of Boretto are also different and the Wnt pathway activation is not universally required in the case of ectocervical stem cells.
This argument has been fully considered, but was not found persuasive since 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). Furthermore, Boretto shows that Wnt3a is an essential factor that controls stemness in the organoid cultures (Boretto, discussion). Thus, 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.
Conclusion
No claims 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 extension fee 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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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
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