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 .
Election/Restrictions
Applicant’s election of Group 1, claims 1-5, 7, 10-11, 13-17 and 26-27 in the reply filed on April 15, 2024 is acknowledged. Applicant has not indicated traversal therefore the election is being treated as without traverse.
Claims 19-21 and 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 15, 2024.
Claims 1-5, 7, 10-11, 13-17 and 26-27 are examined on the merits.
Priority
The instant application is a 35 U.S.C 371 national stage filing of the International Application No. PCT/EP2021/067543 filed on June 25, 2021. The instant application claims foreign priority under 35 U.S.C 119(a)-(d) to British Patent Application GB2009808.3, filed on June 26, 2020. Receipt is acknowledged of a certified copy of the foreign patent application in the original language as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 17, 2023 and March 30, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections to the Drawings
The drawings are objected to because:
FIG 2A: The specification indicates that the legend of FIG 2A is in color (Pg. 10, last para.), however, the images are in black and white.
FIGs 3-4 reference correlation density plots which appear to be intended for color, however the drawings are in black and white.
FIG 7: The specification indicates that the FIG 7 is in color (Pg. 11, last para.) with red, blue, and green indicating the number of mutations due to different factors, however, the images are in black and white.
FIGs 9-11 appear to show a color heatmaps, however the images are in black and white.
FIG 12A appears to show a comparison of organoid lines, however the figure and legend do not allow for determination of one organoid line from another.
FIG 13A-H: the specification indicates that the groups of organoids in various conditions are indicated by colors (i.e., green and orange). However the figures are in black and white.
This is not intended to be a complete list. It is recommended that Applicant review the specification and drawings for other references to color drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on Pg. 12 (Figure 10 caption), Pg. 45, Pg. 46, and Pg. 68. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms Cultrex (Pgs. 17-19), Matrigel (Pgs. 18-19, 23-24), Corning (Pgs. 19, 23, 34, 43), B-27 (Pg. 25), Glutamax (Pg. 25), Nunclon (Pg. 32-33), ThermoScientific (Pg. 33), Sphera (Pg. 33), CellStar (Pg. 33), CoStar (Pg. 43) which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. This is not intended to be a complete list. It is recommended that Applicant carefully review the specification for other trade names or marks.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
The instant claims recite “a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml”. Based on Applicant’s instant specification, this is interpreted as intending to refer to commercial hydrogel compositions such as BME and Matrigel, which Applicant discloses have total protein concentrations between 12-18 mg/ml and 8-12 mg/ml (standard) or 18-22 mg/ml (high protein), respectively (Pg. 19, 1st para.) and not to the physical structural characteristics (i.e., gel-like) which one of ordinary skill in the art would envision based on the term hydrogel. Given the low concentration of complex protein hydrogel instantly claimed, it is expected that compositions comprising complex protein hydrogels such as BME or Matrigel at concentrations as low as 2% v/v would exhibit the physical properties of a liquid solution and not a hydrogel as the term is understood by a skilled artisan.
Claim Rejections - 35 USC § 112(b)
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, 3-5, 10, 13-15, and 17 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) which may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation in step (i) of a population of organoid progenitor cells or organoids, and the claim also recites culturing the population of organoids in step (ii) which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
Claims 3, 10, and 15 recite the limitation “the concentration of a scaffold matrix that is usable to culture organoids embedded in domes of the scaffold matrix” which is a relative term which renders the claim indefinite. A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989). As instantly claimed, these claims recite concentrations of claimed scaffold matrix which are defined by “concentrations of scaffold matrix useable to culture organoids…” which would vary based on individual specific scaffold matrices defined as “usable to culture organoids”. Thus, the claims are indefinite because the relationship of parts is not based on any known standard for culturing organoids embedded in domes. See MPEP 2173.05(b)(II).
Claim 4, which is dependent on claim 1, recites the limitation "the population" in line 1. Claim 1 recites both “an expanded population of organoids” and “a population of organoids”. As claimed, it is unclear to what population “the population” is intended to refer, rendering the claim indefinite. Appropriate correction is required.
Claim 4 recites a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation of a population of organoids or organoid progenitors, and the claim also recites a population of organoids which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
Claim 5 includes the phrase "such as" in lines 4-5 which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 13 contains the trademark/trade names Cultrex BME and Corning Matrigel. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a scaffold matrix and, accordingly, the identification/description is indefinite.
Claim 13 includes the phrase "such as" in line 3 which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 14 contains the trademark/trade name Cultrex BME. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a scaffold matrix and, accordingly, the identification/description is indefinite.
Claim 17 contains the trademark/trade names B-27 and Glutamax. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe media supplements and, accordingly, the identification/description is indefinite.
Claim 17 includes the phrase “such as” in lines 3, 4, 5, 6, and 9 and "for example" (e.g.) in line 4 which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2, which depends from claim 1, recites the method of claim 1 which comprises the same steps as claim 1 with the limitation that the organoids or organoid progenitor cells are mixed with a composition comprising a culture medium and a scaffold matrix. The step of mixing organoids or organoid progenitor cells with the claimed composition appears to be implicit to the recitation in claim 1 of culturing the population of organoids in a composition comprising a culture medium and a scaffold matrix. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 7, 10-11, 13, 15-17, and 26-27 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Kakinuma et al (US 20200071676, found in IDS dated 03/17/2023, hereafter “Kakinuma”) as evidenced by Corning Matrigel (Corning Matrigel Basement Membrane Matrix datasheet found in IDS dated 03/17/2023 and Cultrex BME (Cultrex Reduced Growth Factor Basement Membrane Extract datasheet found in IDS dated 03/17/2023).
With regard to claim 1, Kakinuma discloses a method of producing a cell mass by 3D culture of primary cancer cells which can be derived from a patient tumor (Paras. [0019], [0051], which is considered to reasonably read on organoid progenitor cells or organoids, in a medium containing 5% (v/v) or less extracellular matrix, which is considered to reasonably read on a scaffold matrix which is present in a composition comprising culture medium equivalent to a concentration between 2% (v/v) and 18% (v/v), (Paras. [0022], [0051]). Kakinuma discloses that the extracellular matrix can be Matrigel or Cultrex BME (Para. [0064]), which are both considered to reasonably read on a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml, based on the definition of a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml as provided in the instant specification (Pg. 19, 1st para.) and as evidenced by Corning Matrigel and Cultrex BME data sheets.
With regard to claim 2, Kakinuma discloses that the organoid progenitor cells or organoids can be mixed with a composition comprising a culture medium and a scaffold matrix (i.e., extracellular matrix) in any order (Para. [0062]).
With regard to claim 3, Kakinuma discloses that the scaffold matrix which is a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml is present at a concentration of 5% (v/v) or less (Para. [0022], see also Figs. 2, 3-1, 3-2, 3-3).
With regard to claims 4 and 5, Kakinuma discloses that the culturing is performed in a low adhesive cell culture substrate to enable 3D suspension culture of cells and that the low adhesive cell culture substrate can be Corning ULA (i.e., ultra low attachment) (Para [0055], see also Fig. 1).
With regard to claim 7, Kakinuma discloses that the culture can be performed for a time which is appropriate for the test method of interest, for example 30 days, which is considered to reasonably read on at least 4 weeks (Para. [0066]).
With regard to claim 10, Kakinuma discloses that the scaffold matrix which is a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml is present at a concentration of 5% (v/v) or less (Para. [0022], see also Figs. 2, 3-1, 3-2, 3-3).
With regard to claim 11, Kakinuma discloses that the scaffold matrix which is a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml is present at a concentration of 5% (v/v) or less (Para. [0022], see also Figs. 2, 3-1, 3-2, 3-3). Therefore Kakinuma’s scaffold matrix comprises a complex protein hydrogel having a protein concentration between 0.6 mg/mL (i.e., 5% of 12 mg/ml) and 0.9 mg/mL (i.e., 5% of 18 mg/ml). Additionally, based on Applicant’s instant specification, Cultrex BME and Matrigel are considered to be complex protein hydrogels (Pg. 18, last para. and Pg. 19, 1st para.). Applicant’s specification also states that a in a composition comprising a culture medium and Cultrex BME at a concentration between 2% (v/v) and 18% (v/v), the protein concentration from the complex protein hydrogel may be between 0.24 mg/ml and 3.24 mg/ml (Pg. 19, lines 24-28). Therefore, Kakinuma’s disclosure a composition comprising culture medium and a 5% (v/v) of scaffold matrix which can be Cultrex BME is considered to reasonably read on a complex protein hydrogel present in a composition at a concentration that results in the protein concentration from the complex protein hydrogel of between 0.25 mg/ml and 3.24 mg/ml.
With regard to claim 13, Kakinuma discloses that the extracellular matrix can be Cultrex BME or Corning Matrigel (Para. [0064]).
With regard to claim 15, Kakinuma discloses that the scaffold matrix which is a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml is present at a concentration of 5% (v/v) or less (Para. [0022], see also Figs. 2, 3-1, 3-2, 3-3).
With regard to claim 16, Kakinuma discloses that the medium used for the 3D cell culture can be RPM11640 or MCDB medium, which is considered to reasonably read on a chemically defined medium (Para. [0067]).
With regard to claim 17, Kakinuma discloses that the medium use can comprise additional compounds like growth factors and such insulin, which is considered to reasonably read on a hormone. (Para. [0067]).
With regard to claims 26 and 27, Kakinuma discloses that the primary tumor tissue used for 3D culture may be a tissue fragment comprising cancer cells which are of mammalian origin and can be cancer cells from various tumor types, including breast cancer (Para. [0056]).
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Kakinuma et al (US 20200071676, found in IDS dated 03/17/2023, hereafter “Kakinuma”) in view of Jin et al. (2018, Organoids: An intermediate modeling platform in precision oncology. Cancer Letters, 414, 174-180, hereafter “Jin”).
With regard to claim 14, Kakinuma teaches a method of producing a cell mass by 3D culture of primary cancer cells which can be derived from a patient tumor (Paras. [0019], [0051], which is considered to reasonably read on organoid progenitor cells or organoids, in a medium containing 5% (v/v) or less extracellular matrix, which is considered to reasonably read on a scaffold matrix which is present in a composition comprising culture medium equivalent to a concentration between 2% (v/v) and 18% (v/v), (Paras. [0022], [0051]). Kakinuma teaches that the extracellular matrix can be Matrigel or Cultrex BME (Para. [0064]), which are both considered to reasonably read on a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml, based on the definition of a complex protein hydrogel having a protein concentration between 12 and 18 mg/ml as provided in the instant specification (Pg. 19, 1st para.) and as evidenced by Corning Matrigel and Cultrex BME data sheets. Kakinuma teaches that the primary cancer cells can be from various tumor types, including esophageal cancer.
While Kakinuma teaches use of various scaffold matrices, including Cultrex BME and Cultrex RGF BME (Para. [0064]), Kakinuma is silent as to use of Cultrex BME type 2.
Jin, in a review, teaches that BME-2 is a commonly used matrix for culture of organoids from various cancers including esophageal cancer (see Table 1).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to choose BME-2 as the scaffold matrix used for the culture of tumor organoids as taught by Jin for use in the method of culturing organoids in a medium comprising a scaffold matrix which can be Cultrex BME as taught by Kakinuma with a reasonably expectation of success. A skilled artisan would have been motivated to choose BME-2 since Jin teaches that BME-2 can be used as a matrix for various tumor organoid cultures, especially if a skilled artisan wanted to culture tumor organoids from esophageal cancer. One having ordinary skill in the art would have had a reasonable expectation of success as both Kakinuma and Jin teach culture of organoids in medium comprising a BME matrix.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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