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 .
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: definition of the term “tumorsphere”. The specification simply states that the MOS may contain tumorspheres and that they may be generated in a desired size, quantity, or both. (Pg 2-3, Summary) The specification goes on to define further parameters for said tumorspheres, but fails to actually define what differentiates a tumorsphere from a patient-derived MOS which comprises cancer cells harvested from a biopsy.
Claim Interpretation
The Specification fails to fully define “tumorspheres”, however the Specification does state that the MOS of the claimed invention may comprise “tumorspheres and/or tumorsphere-like structures in the presence of tumor-resident immune cells”. (Pg 3-4, Summary) As such, art reading on patient-derived organoids comprising cells of the immune system commonly found in the tumor microenvironment, such as macrophages and dendritic cells, will read on the generation of “tumorspheres”.
Claim Rejections - 35 USC § 112
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.
Claim 15 is 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 15 recites the limitation " tumorspheres" in the second half of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 13 introduces the limitation of inclusion of a “tumorsphere” to independent claim 1, however claim 15 also depends on claim 1. As such, there is insufficient antecedent basis for claim 15 for a person skilled in the art to understand what a “tumorsphere” is referring to. It is recommended that the Applicant amend claim 15 to depend from claim 13, as that is where the concept of a tumorsphere is introduced.
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 (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 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.
Claim(s) 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (US 2020/0377861 A1) in view of Menche et al. (Strategies for genetic manipulation of adult stem cell-derived organoids, 2021)
Regarding claims 1 and 2: Shen teaches a method of generating patient-derived micro-organospheres (hereafter PMOS) and methods of using them in personalized therapy. (57) Importantly, Shen discloses that the PMOS of the claimed invention may also be referred to as “droplets”. (0012) Shen details success at deriving PMOS from cells of patients (0011) of various cancers such as breast, colon, uterine, kidney, and lung from both primary and metastatic sites. (0013) Shen further teaches that the PMOS are suitable for use in culture. (0021) Shen fails to teach use of introduction of a virus into the PMOS culture.
Menche teaches that the access of genetic manipulation enables the investigation of the molecular mechanisms controlling cell fate regulation, cell to cell interactions, and cell differentiation while at the three dimensional level where it is possible for cells to self-organize and differentiate. (Pg 1483, Abstract) Menche details multiple pathways to successful genetic modification resulting in a confirmed clonal line or the expansion of said modified organoids, as shown in Figure 3 below:
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Importantly, Menche teaches that retro or lentiviral transduction is a highly efficient method for the stable genetic modification of organoids. (Pg 1486, Methods for the delivery and propagation of transgenes in organoids)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Menche of use of lentiviral transfection of organoids to express genes transfected by said virus with the PMOS protocol taught by Shen. One would have a reasonable expectation of success and motivation to do so based on the teachings of Menche, who state that viral transduction is a highly efficient and stable method of genetic modification of organoids.
Regarding claim 3: Shen teaches that the PMOS have a diameter of between 50-500 uM. (0023)
Regarding claim 4: Shen teaches that the PMOS comprise between 1 and 200 dissociated cells distributed therein. (0023)
Regarding claims 5-8: Shen teaches that the PMOS may be generated from a patient biopsy obtained with an 18-gague core biopsy (0009) and may be from primary tumors. (0011)
Regarding claims 9 and 10: Shen teaches successful production of PMOS from cancers of the colon, kidney, lung, uterus, bone, lung, breast, esophagus, and skin from both primary and metastatic sites. (0013)
Regarding claims 11 and 12: Shen teaches that the PMOS may be created from patient-derived xenografts (0011) and gives multiple examples of use of colorectal cancer (CRC) tissue for the creation of said PMOS. (0064-0066)
Regarding claims 13, 15, and 16: Shen teaches that the PMOS may include cells of the immune system such as dendritic cells and macrophages in addition to stem cells, progenitor cells, or somatic cells. (0019) As discussed in the Claim Interpretation section above, this is considered to read on the PMOS comprising tumorspheres.
Shen further teaches the need to generate patient derived models with smaller and more uniform sizes that have better controllability for cell numbers per unit (0009) and that the number of cells and diameter of the PMOS generated is able to be controlled within 5%-30% of the target number. (0012) This reads on claim 15 regarding configuring the seeding density of said PMOS to the desired quantity, size, or both.
Furthermore, this reads on the method of claim 16 of determining the number of droplets by dividing a number of viable cells by a number of cells per droplet. Following the method of Shen as taught in paragraph 0100, one skilled in the art would have to count viable cells and portion said cells out per droplet in order to have so narrow a window of control over the number of cells per droplet and the size of said droplets. In addition, it is an extremely common laboratory practice throughout the art to not only do a live/dead cell count prior to plating cells, but also to divide the number of cells per intended wells (or in this case, organoids) in order to ensure accurate plating density. Therefore, in following the method of claim 1 and viewing in light of the teachings of Shen, it is inherent that it is required by the method of claim 1 to determine a number of droplets by dividing a number of viable cells by a number of cells per droplet.
Regarding claim 14: Shen teaches a seeding density of less than 100 cells per micro-organosphere. (0100)
Regarding claims 17-20: Shen teaches in Example 4 of the claimed invention the use of PMOS to run a panel of chemotherapeutic agents on generated PMOS in order to determine the toxicity level of various chemotherapeutic agents for a particular patient-derived tumor. (0174) It is known in the art that the vast majority of chemotherapeutic agents are considered to be small molecules. The PMOS of Example 4 showed the most toxicity to Pazopanib. While Pazopanib is not a chemotherapeutic agent, Example 2 of the claimed invention tests the effectiveness of the chemotherapeutic agent Oxalipalitin on PMOS and the results predicted that the specific tumor of which the PMOS were derived would be resistant to Oxalipalitin at all dose ranges examined. (0171)
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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