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 .
DETAILED ACTION
The examiner for this Application has changed. Please direct all future correspondence to Patent
Examiner, Katriel B Kasayan, AU 1634. Additional contact information can be found at the end of this
paper.
The text of those sections of Title 35, U.S. Code not included in this section can be found in a prior Office Action.
This action is in response to papers filed on September 10, 2025. Pursuant to the claims filed on September 10, 2025, claims 10, 11, 13, 17-20, and 38-42 are currently pending. No claims were amended, canceled or newly added by Applicants’ amendment filed on 9/10/2025.
Therefore, claims 10, 11, 13, 17-20, and 38-42 are currently under examination to which the following grounds of rejection are applicable.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). International Application PCT/US2019/056577 was filed on October 16, 2019. The International Application claims priority to US Provisional 62/746,296 filed October 16, 2018.
Thus, the earliest possible priority for the instant application is January 4, 2019.
Response to Arguments
Maintained Objections/Rejections in Response to Applicants’ arguments or amendments: Claim Rejections - 35 USC § 103
Claims 10, 11, 13, 17, 18 and 38- 40 remain rejected under 35 U.S.C. 103 as being unpatentable over of Boj et al. (Cell, 2015, 160, pp. 324-338) (ref. of record) in view of Makareeva et al. (Cancer Research, 2010, 70(11), pp. 4366-4374) (ref. of record) and Sachs et al. (US 2017 / 0342385 A1, 2017) (ref. of record), as evidenced by Millipore Sigma ("DMEM/F- 12 PLUS Basal Medium" product sheet, accessed on March 8, 2024) (ref. of the record).
Regarding claim 10, Boj teaches methods to generate models of pancreatic cancer organoids in a three-dimensional cell culture by embedding the cells in Matrigel (extracellular matrix) in a cell culture medium (pg. 335, left col., par. 4; right col., par. 2, “ The material [Human Pancreatic Tumor and Normal Organoid Culture] was further digested with TrypLE (Gl8CO) for 15 min at 37°C, embedded in GFR Matrigel, and cultured in human complete medium)”. Boj also discloses that pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation and exhibit ductal- and disease-stage-specific characteristics, which are all important to properly investigate cancer pathogenesis and recapitulate the full spectrum of tumor development (abstract; pg. 325, left col., par. 2-3). Therefore, Boj generated a cancer model system based on 3D organoids to accurately recapitulate physiologically relevant aspects of disease progression in vitro including examination of cell viability via a proliferation assay (Supplemental Information S1, para 2).
However, Boj fails to teach the medium further comprises exogenous collagen I homotrimers.
Makareeva teaches that carcinomas present alpha(I)3 homotrimers, a type I collagen isoform normally not present in healthy tissues. Makareeva teaches matrix metalloproteinases (MMP) are produced by cancer cells and cancer-associated fibroblasts produce for degrading stromal collagen at the leading edge of tumor invasion.” (abstract). Additionally, Makareeva discloses that “MMP-resistant homotrimers were produced by all invasive cancer cell lines tested, both in culture and in tumor xenografts” (abstract). Moreover, “Furthermore, we confirmed an enhanced proliferation and migration of invasive cancer cells on the surface of homotrimeric versus normal (heterotrimeric) type I collagen fibers” (abstract). Specifically, Makareeva exemplifies culturing cancer cells in a culture medium prepared with a mixture of exogenous collagen I homotrimers and heterotrimers secreted by normal dermal fibroblasts (CRL-2127) and nine cell lines from different types of cancer, respectively, pg. 4370-4371, left col., par 1; Supplementary Fig. S3-A) . Makareeva compares cancer cell interactions with heterotrimer and homotrimer collagen fibers prepared under physiologic conditions from mouse-tail tendon type I collagen fibers and observed faster migration and proliferation of cancer cells on the homotrimer matrix (page 4372, col. 1, para 1). Moreover, Makareeva discloses purified type I collagen from tumors produced in athymic nude mice by LOX-IMVI, PC-3, and MDA-MB-231 cells and determines peaks of murine heterotrimers (page 4371, col2). Makareeva discloses that type I collagen homotrimer fibers have distinct mechanical properties, which play an important role in malignancy, affecting the behavior of cancer cells - e.g., higher rigidity of the homotrimer fibers might contribute to the faster proliferation and migration of cancer cells. Makareeva adds that potential differences in binding of proteoglycans, cytokines, and other matrix molecules to homotrimer fibers may also affect cancer microenvironment (pg. 4372, Discussion left col.). Makareeva teaches that culturing cancer cells in the presence of collagen I homotrimers enhances proliferation and migration (Abstract, “cancer cells may use homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cells whereas surrounding normal stromal collagens are cleaved.”).
It would have been obvious to a person of ordinary skill in the art to combine the teachings of Makareeva regarding culturing cancerous cells in the presence of exogenous collagen I homotrimers to enhance cancer proliferation and migration with the teachings of Boj regarding the preparation of human pancreatic tumor organoids in a tree-dimensional cell culture to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine both references since Makareeva teaches (i) culturing cancer cells in culture medium producing collagen I homotrimers, (ii) reconstituted heterotrimer and homotrimer collagen fibers to study proliferation and migration of cancer cells , (iii) type I homotrimer synthesis is produced by purified type I collagen from tumors and (iv) that type I collagen homotrimers, being part of the natural cancer microenvironment, have distinct mechanical properties that affect the behavior of cancer cells and the cancer microenvironment, while Boj taught a model system based on 3D organoids to accurately recapitulate physiologically relevant aspects of disease progression in vitro. Therefore, culturing cancer cells in three-dimensional cell culture with an extracellular matrix, as taught by Boj, in the presence of medium comprising exogenous collagen I homotrimers produced by cancer cells , as taught by Makareeva, or added to the culture medium comprising cancer cells would allow for an improved method for the rapid generation of an organoid system that resembles the molecular and cellular properties of cancer to further investigate the role of collagen I homotrimers in cancer proliferation and migration, therapeutic targets and for other purposes in a physiologically relevant manner.
In addition, one of ordinary skill in the art would have had a reasonable expectation of success since cancer cells had been successfully cultured in the presence of exogenous collagen I homotrimers produced by cancer cells and type I homotrimer synthesis is produced by purified type I collagen from tumors , as taught by Makareeva. Furthermore, 3D cancer organoids had been developed and their benefits and potential uses to advance cancer studies were described in the prior art, as taught by Boj.
Regarding claim 11, the combined teachings of Makareeva and Boj render obvious the claimed methodology of claim 10 . Moreover, Boj used human pancreatic cancer tissues (primary cancerous cells, pp. 335 col 1 “Pancreatic cancer tissues and adjacent normal pancreas were obtained from patients” ).
Regarding claim 13, the combined teachings of Boj and Makareeva render obvious the method of claim 10. Moreover, Boj also used murine primary pancreatic ductal adenocarcinoma cells (pg. 325, right col., par. 3; pg. 327, left col., par. 2).
Regarding claims 17 and 18, the combined teachings of Boj and Makareeva render obvious the method of claim 10. Moreover, Boj teaches culturing the organoids in Matrigel®, which is a basement membrane preparation from Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells that comprises laminin, entactin and collagen IV, as evidenced by Sachs (pg. 335, left col., par. 4; right col., par. 2). Sachs describes different types of ECM and teaches that Matrigel® is a basement membrane preparation from Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells comprising laminin, entactin and collagen IV (0178 in right col.; 0180).
Regarding claim 38, the combined teachings of Boj and Makareeva render obvious claim 10. Moreover, Boj discloses performing the human pancreatic tumor organoid culture in AdDMEM/F12 medium (pg. 335, right col., par. 2), which is an advanced basal medium used in low-serum or serum-free media formulations for stem cell and 3D organoid cell cultures, as evidenced by Millipore Sigma. Boj does not disclose adding serum to the human pancreatic tumor organoid culture medium. Therefore, Boj used a serum-free medium.
Regarding claim 40, the combined teachings of Boj and Makareeva render obvious claim 10. Moreover, Boj discloses culturing murine neoplastic pancreatic ductal organoids in DMEM media containing 1 % FBS (supplemented with serum) (pg. 335, left col., par.4).
Accordingly, it would have been obvious to one of ordinary skill in the art at the effective time of filing to use a culture medium comprising serum replacement for culturing cancerous cells in a three-dimensional cell culture as claimed since methods developed for culturing three-dimensional organoids, as taught by Sachs, disclosed embodiments in which serum replacement could be added to the medium. A person of ordinary skill in the art would have had a reasonable expectation of success in using serum-replacement for culturing organoids since serum replacement is one of the different alternatives disclosed in the prior art for supplementing the culture medium.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
***
Claim 20 remains rejected under 35 U.S.C. 103 as being unpatentable over of Boj et al. (Cell, 2015, 160, pp. 324-338) (ref. of record) in view of Makareeva et al. (Cancer Research, 2010, 70(11), pp. 4366-4374) (ref. of record) and Sachs et al. (US 2017 / 0342385 A1, 2017) (ref. of record), as evidenced by Millipore Sigma ("DMEM/F- 12 PLUS Basal Medium" product sheet, accessed on March 8, 2024) (ref. of the record) as applied to claims 10, 11, 13, 17, 18 and 38- 40 above, in further view of Thakuri et al. (Advanced Healthcare Materials, 2017).
The teachings of Makareeva, Boj and Sachs can be found in the previous rejection above. With respect to claim 20, the teachings of Makareeva, Boj, and Sachs fail to teach a method as recited in claim 10 where the extracellular matrix is synthetic.
However, Thakuri discusses natural and synthetic biomaterials to culture cancer cells as spheroids and organoids (see abstract). Thakuri teaches that synthetic materials can be conveniently engineered with defined properties such as stiffness, porosity and presentation of specific signaling molecules present in tumor microenvironments (pg. 2, left col., par. 2; Fig. 1 ). Thakuri discusses the advantages of different natural and synthetic materials for culturing cancer cells and forming organoids that recapitulate the native environment of cells and tumors (see whole document). Moreover, Thakuri teaches that synthetic biomaterials for organoid cultures can be engineered to simulate specific micro environments compared to natural in vivo structures (pp. 1700980, col 1, “On the other hand, synthetic materials such as polyethylene glycol (PEG), poly(lactic-co-glycolic) acid (PLGA), and polycaprolactone (PCL) can be conveniently engineered with defined properties such as stiffness, porosity, and presentation of specific signaling molecules present in tumor microenvironments. The ability to engineer and control these properties provides novel approaches to elucidate effects of defined mechanical and biochemical cues on cancer cells.”)
Accordingly, it would have been obvious to a person of ordinary skill in the art to substitute Thakuri’s synthetic extracellular matrix for Makareeva’ s extracellular matrix in a method for obtaining and/or culturing organoids with a reasonable expectation of success, particularly to control and define the properties of the microenvironment where the organoids will grow. In addition, one of ordinary skill would have a reasonable expectation of success since natural and synthetic materials are commonly used have been shown to effective for the same purpose, as taught by Thakuri. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
***
Claims 41 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over of Boj et al. (Cell, 2015, 160, pp. 324-338) (ref. of record) in view of Makareeva et al. (Cancer Research, 2010, 70(11), pp. 4366-4374) (ref. of record) and Sachs et al. (US 2017 / 0342385 A1, 2017) (ref. of record), as evidenced by Millipore Sigma ("DMEM/F- 12 PLUS Basal Medium" product sheet, accessed on March 8, 2024) (ref. of the record) as applied to claims 10, 11, 13, 17, 18 and 38- 40 above, in further view of Agorku et al. (Miltenyi Biotec, 2017) (ref. of record).
With regard to claim 1, the combined teachings of Makareeva, Boj and Sachs render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 10. The teachings of can be found in the previous rejection above. Moreover, Boj discloses obtaining the cancerous cells from human tumor tissue (pg. 335, right col., par. 2) Regarding claim 42, Boj discloses generating organoids from human cancerous tissue obtained by fine-needle biopsy (pg. 330, left col., par. 1 ).
However, Boj discloses that the biopsy organoids were not dissociated prior to suspension in Matrigel® (pg. pg. 330, left col., par. 1).
However, Agorku describes a workflow to enable the isolation and analysis of tumor cells from cancer samples and tumor cells obtained by biopsy (see background). Agorku discloses that analysis of tumor tissue obtained by needle biopsies yield only small amounts of tissue, which in many cases do not suffice for dissociation (Background, left col.). Agorku further discloses that by using different biopsy methods and needles available, it is possible to obtain high yield and optimal tissue dissociation (Background, left col.).
Accordingly, it would have been obvious to one of ordinary skill in the art at the effective filing date to obtain human tissue by biopsy and dissociate the cancerous cells from the obtained human tissue since dissociation of cells from biopsy was described in the art for further analysis and cultivation of the cells, as taught by Agorku. A person of skill in the art would have been motivated to combine the method taught by Boj comprising the generation of cancer cell organoids from limited amounts of cells provided by biopsies with the teachings of Agorku regarding the use of different biopsy methods and needles available with the purpose of obtaining a high yield and optimal tissue dissociation. Furthermore, one of ordinary skill would have had a reasonable expectation of success because obtaining tissue by biopsy is common practice in the art. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Response to Applicant Arguments as they apply to the rejection of claims 10, 11, 13, 17, 18 and 38- 40 under USC §103
Beginning of page 4 filed on September 10, 2025, Applicants essentially argue the following:
Neither Makareeva nor Boj teach or suggest adding exogenous collagen I homotrimers to culture organoids. Furthermore, it would not have been obvious since the prior art teaches that cancer cells produce collagen I homotrimers, as taught by Makareeva.
Makareeva does not support a role for collagen I homotrimers in the progression of cancer in the natural microenvironment of PDA cells such that a person of ordinary skill in the art would see fit to substitute Makareeva's 2D cell culture with Boj's 3D organoid culture.
Boj emphasizes the importance of studying the natural, in vivo progression of pancreatic ductal adenocarcinoma, and to not speed the progression and proliferation of cells.
Claim 20 depends from claim 10. As explained above, claim 10 is patentable over Makareeva, Boj, Sachs, and Millipore Sigma. The Office relies on Thakuri as allegedly describing natural and synthetic biomaterials to culture cancer cells as spheroids and organoids. Id. at 8. The Office has not shown that Thakuri would supply the deficiencies of Makareeva, Boj, Sachs, and Millipore Sigma.
Claims 41 and 42 depend from claim 10. As explained above, claim 10 is patentable over Makareeva, Boj, Sachs, and Millipore Sigma. The Office relies on Agorku as allegedly describing a workflow to enable the isolation and analysis of tumor cells from cancer samples and tumor cells obtained by biopsy. Id. at 9-10
In response to the argument, it has been fully considered but is not persuasive due to the following reasons:
Regarding 1), with regard to Applicant’s argument that Boj does not teach the entire claimed subject matter, the Examiner agrees. However, Boj is not applied alone, but in combination with Makareeva and Sachs, as evidenced by Millipore Sigma, and the claimed invention becomes obvious when the references are considered together as a whole rather than each alone. Boj teaches a three-dimensional organoid culture for studying thew pathogenesis of pancreatic ductal adenocarcinoma (PDA) (pp. 325, “We developed 3D organoids from normal and malignant murine pancreatic tissues and used this model system to investigate PDA pathogenesis”), but fails to teach the limitation comprising the collagen I homotrimers. Makareeva teaches that the collagen I homotrimers are produced by cancer cells and play a significant role in alter cell behavior, cell proliferation, migration and tumor microenvironment (pp. 4372 col 1, “In addition to MMP resistance, type I collagen homotrimer fibers have distinct mechanical properties…contribute to faster proliferation and migration of cancer cells…affect cancer microenvironment”). Although the Applicant notes that “mature collagen-producing cells may have a mechanism for preventing the α1(I) homo trimer formation” on page 4372 of Makareeva, this phrase is only directed towards already differentiated and mature cells, and not cancer cells. Moreover, Makareeva discuses that there is homotrimer synthesis in “embryonic cells, dedifferentiated cells, nonosteogenic bone marrow cells , chemically transformed cells, cancer cells, and stressed mesangial cells has been well documented” (pp. 4372). Although collagen I homotrimers cannot be produced by mature-collagen producing cells, it emphasizes that homotrimer formation is biologically relevant to cancer cells and cancer. Furthermore, Makareeva teaches reconstituted heterotrimer and homotrimer collagen fibers to study proliferation and migration of cancer cells and type I homotrimer synthesis is produced by purified type I collagen from tumors. Therefore, a person with ordinary skill in the art would have been motivated to incorporate cancer cells producing collagen I homotrimers in a 3 -dimensional cell culture or supplement said medium comprising cancer cells with purified type I collagen from tumors.
Regarding 2), In contrast to Applicants’ remarks, Makareeva is not cited to substitute Makareeva’s 2D cell culture with Boj's 3D organoid culture. Makareeva is cited to remedy the deficiencies of Boj in relation to supplementation of collagen I homotrimers in the 3-D model of Boj. Makareeva demonstrates the invasive cancer cells use homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cancer cells. Moreover, cancer cells proliferate and migrate in a 2-D model and in a 3-D model. The presence of collagen I homotrimers in a 2-D model enhances proliferation and migration of cancer cells, so the presence of collagen I homotrimers in a 3-D should be reasonably expected to promote proliferation and directed migration of the cancer cells for the same reason it does in a 2-D model . Furthermore, Boj teaches that they “used this model system [3-D organoids] to investigate PDA pathogenesis” (pp.325) as it is physiologically similar and more inexpensive to animal models (pp. 325 col 1, “[Genetically engineered mouse models, GEMMs] are expensive and time consuming). Moreover, Boj discloses that two-dimensional culture conditions do not support untransformed, neoplastic pancreatic cells, but well-developed 3D cell cultures using neoplastic pancreatic organoids can address these issues (pp. 325, “two-dimensional (2D) culture conditions, [which] do not support growth of untransformed, nonneoplastic pancreatic cells. Three-dimensional (3D) culture strategies have been developed to study normal, untransformed cells…to address this deficiency, we sought to generate normal and neoplastic pancreatic organoids”). A skilled artisan would have been motivated not only to supplement collagen I homotrimers in the 3-D model of Boj but also to transition from a two-dimensional cell culture to a three-dimensional cell culture taught by Boj, as a 3D organoid culture would be more physiologically relevant compared to a monolayer of cells.
Regarding 3), it is noted that Boj states that “[they] developed 3D organoids from normal and malignant murine pancreatic tissues and used this model system to investigate PDA pathogenesis” (pp. 325 col 1), however this only reveals that they utilize the organoid system to study disease, but does not explicitly discourage the modification of the tumoroid model, or that the organoid model has to be in a fixed condition. Moreover, Makareeva emphasizes that collagen I homotrimers play a significant role in the cancer microenvironment (pp. 4372 col 1, “In addition to MMP resistance, type I collagen homotrimer fibers have distinct mechanical properties…contribute to faster proliferation and migration of cancer cells…affect cancer microenvironment”). Makareeva also teaches that cancer cells produce these homotrimers, thus inherently making them present in the tumor’s microenvironment (pp. 4372 col 2, “Consistent with our hypothesis for the role of type I collagen homotrimers in cancer invasion, the same cancer cells seem to produce a higher fraction of the homotrimers in vivo”). A person with ordinary skill in the art would have been motivated to develop the PDA organoid of Boj and have it to comprise collagen I homotrimers to understand its role in cancer progression. Furthermore, a skilled artisan would have been motivated to incorporate collagen I homotrimers as they are already present in the environment, and would make the organoid model more physiologically accurate.
Regarding 4) Thakuri is relied upon in combination with Sachs, MilliporeSigma, Boj and Makareeva for the teachings regarding using synthetic extracellular matrix. One cannot show obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 G2d 413,208 USPQ 871 (CCPA 1981); In re Merck & Co.¸ 800 F.2d 1091, 231 375 (Fed. Cir, 1986).
Moreover, a person with ordinary skill in the art would have been motivated to use a synthetic extracellular matrix as their basis for a three-dimensional organoid model as defined properties such as stiffness, porosity, and/or signaling molecules present within the matrix can be controlled or engineered to simulate niche tumor microenvironments. Therefore, a skilled artisan would have been motivated to modify the three-dimensional organoid taught by Boj to incorporate synthetic biomaterials and to control the synthetic extracellular matrix to mimic the same properties as the tumor microenvironment.
Regarding 5), Agorku is relied upon to remedy the rejection with Sachs, MilliporeSigma, Boj and Makareeva for the teachings regarding that the cells are dissociated from human tissue and that the human tissue is from a biopsy. One cannot show obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 G2d 413,208 USPQ 871 (CCPA 1981); In re Merck & Co.¸ 800 F.2d 1091, 231 375 (Fed. Cir, 1986). Arguments presented by applicant cannot take the place of evidence in the record. applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. See MPEP 2145.
Moreover, it would have been obvious for one with ordinary skill in the art to obtain human tissue from a biopsy and disassociate the cancerous cells from the obtained tissue, as it was a method for cultivation of cells at the time of the claimed invention. A skilled artisan would have been motivated to combine the three-dimensional organoid culture taught by Boj with the cell cultivation method of Agorku for the purpose of utilizing different methods for generating organoid cultures. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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/KATRIEL BARCELLANO KASAYAN/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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