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 Claims
Applicant's amendments filed 11/4/2025 have been entered and considered. Claims 46-63, and 66 are pending, of which claims 46-49, 58-63, and 66 are being considered on their merits. Claims 50-57 remain withdrawn from consideration. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
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.
Claims 46-49, 58-63, 66 are rejected under 35 U.S.C. 103 as being unpatentable over Sato et al (U.S. PGPUB 20120196312; 8/24/2021 IDS) in view of Nigam et al (WO 2014/066649; 8/24/2021 IDS).
Regarding claims 46-49, 58-63, Sato teaches an organoid comprising a population of adult epithelial stem cells and differentiated progeny of the adult epithelial stem cells ( “adult epithelial stem cells” are necessarily specific to a tissue reading on “tissue-specific”) in a culture medium, wherein said organoid has a cyst-like structure with a central lumen (see paragraphs [0010]-[0012], [0060], [0085], Examples, and claims 1-4, 7 & 9-15). Under the heading “Organoid Functions”, the primary reference Sato teaches on paragraph [0181] Preferably, cells and organoids generated according to the invention also possess tissue-specific functions. In paragraph [0199] Sato teaches: The viable cells preferably possess tissue-specific functions, or characteristics of tissue-specify functions, as described above. Paragraphs [0109], [0129] & [0149] of Sato also teach “tissue-specific”.
Sato teaches the culture medium may comprise FGF7 (FGFR2b ligand), noggin (reads on BMP inhibitor and TGF-beta inhibitor), B27, N-acetylcysteine, Nicotinamide, a ROCK inhibitor, and a p38 inhibitor (see paragraphs [0039]-[0041] and [0189], and claims 1-4, 7 & 9-15). Regarding claims 49, Sato teaches the culture medium is “suitable for” expanding for at least 10 passages (see paragraph [0361]). Regarding claim 66, Sato teaches that the cells formed mammary gland epithelial structures in paragraph [0415] in Example 1.
Sato does not teach the medium comprises neuregulin (ErbB3/4 ligand) or PDGF (claims 46 and 64-65).
Like Sato, Nigam also teaches combining stem cells with factors to induce said stem cells to into a branching bud and that the factors also induce the cells to form tubular structures with lumens (reads on “cyst-like structure” that does not comprise cells) in three-dimensional organoid cultures, and Nigam teaches stem cells, ureteric bud cells and specifically that epithelial bud progenitor cells can be used in this method (paragraphs [0059], [0071]-[0081] and [0085] and claims 1-2 and 5-7). Regarding claims 46 and 64, like Sato, Nigam teaches the factors used for culture include FGF7 (FGFR2b ligand), and that it is further beneficial to also include neuregulin (ErbB3/4 ligand) and PDGF (paragraphs [0071]-[0081] and [0085] and claims 1-2 and 5-7). Nigam also provides in Table 1 in paragraph [0031] that neuregulin can also promote stem cells budding into mammary gland structures. Nigam identifies neuregulin is being beneficial for growth and survival of cells in organoids in paragraph [0009].
It would have been obvious to combine Sato and to include Nigam’s neuregulin and PDGF in Sato’s medium. A person of ordinary skill in the art would have had a reasonable expectation of success in including Nigam’s neuregulin and PDGF in Sato’s medium, because Nigam teaches this media additive can be stem cells from epithelial tissue in form of organoids with lumens. The skilled artisan would have been motivated to include Nigam’s neuregulin and PDGF in Sato’s medium because both references teach cell culture medium for stem/progenitor cells with several overlapping additives, used to form overlapping structures, and Nigam teaches these media additive can be stem cells from epithelial tissue in form of organoids.
As stated above, Nigam teaches including neuregulin, which is the same “ErbB3/4 ligand” as is in the claimed composition (as claimed in dependent claim 58). Additionally, the instant specification identifies neuregulin as having the functional property of being able to induce the heterodimerization of ErbB3 or ErbB4 with ErbB2. Therefore, regarding the functional limitation of independent claim 46 wherein the “ErbB3/4 ligand induces the heterodimerization of ErbB3 or ErbB4 with ErbB2”, since Nigam teaches the same ErbB3/4 ligand, Nigam’s neuregulin reads on having this functional property. Similarly, since Sato teaches including FGF7, which is the same FGFR2b ligand as is in the claimed composition (claim 59), and noggin which is the same BMP inhibitor as is in the claimed composition (claim 61), Sato’s FGF7 and noggin read on having the functional properties of “elicits tyrosine phosphorylation of FRS2α or FRS2β” and “binds to a BMP molecule to form a complex wherein the BMP activity is neutralized”. It is also noted that the instant specification identifies FGF7 and noggin as having these functional properties.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 46-49, 58-63, 66 are rejected under 35 U.S.C. 103 as being unpatentable over Nigam et al (WO 2014/066649; 8/24/2021 IDS) in view of Hisha et al (2013, Sci Rep 3, 3224; reference U).
Regarding claims 46-49, 58-63, 66, Nigam teaches combining stem cells with factors to induce said stem cells to into a branching bud and that the factors also induce the cells to form tubular structures with lumens (reads on “cyst-like structure” that does not comprise cells) in three-dimensional organoid cultures, and Nigam teaches stem cells, ureteric bud cells and specifically that epithelial bud progenitor cells can be used in this method (paragraphs [0059], [0071]-[0081] and [0085] and claims 1-2 and 5-7). Regarding claim 46, Nigam also teaches the source of cells used to ultimately engineer organ tissue need not be derived from the particular organ, and that adult stem cells can be used (paragraphs [0048], [0097] and [0105]). The reference teaches differentiating cells into tissue specific organoids. See claim 19 and [0008]
Nigam teaches that the branching bud can form epithelial tissues (paragraphs [0071]-[0081] and [0085]); reads on “differentiated”. Nigam teaches the factors used in the method include neuregulin (ErbB3/4 ligand), FGF7 and FGF10 (FGFR2b ligands), PDGF (paragraphs [0071]-[0081] and [0085] and claims 1-2 and 5-7). Regarding claims 49 and 64, Nigam’s medium reads on a culture medium is “suitable for” expanding a population of epithelial stem cells for at least 4 or 6 passages. Regarding claim 66, Nigam also provides in Table 1 in paragraph [0031] that neuregulin can also promote stem cells budding into mammary gland structures. Nigam identifies neuregulin is being beneficial for growth and survival of cells in organoids in paragraph [0009].
Nigam teaches that the ureteric bud, also known as the epithelial bud, is the embryonic primordial tissue, that at embryonic day 12 in rats and about 4 weeks into human embryonic development, begins outgrowth of which the branched urinary collecting duct system of the kidney arises (paragraph [0068] and Figure 7). Nigam teaches "progenitor cell" and "stem cell" are used interchangeably in the art and herein (see paragraph [0061]). Regarding claims 46 and 64, given these teachings, Nigam’s stem cells which can form epithelial tissues read on “epithelial stem cells”, Nigam’s embryonic ureteric bud, also known as the epithelial bud, read on “epithelial stem cells”, and Nigam’s epithelial bud progenitor cells read on “epithelial stem cells”.
Nigam does not teach the culture medium comprises noggin (reads on BMP inhibitor and TGF-beta inhibitor). Nigam does not teach the epithelial stem cells are adult epithelial stem cells.
Regarding claim 46, Hisha is drawn to a cell culture system for generating organoids with epithelial layer and a lumen, and Hisha teaches using adult epithelial stem cells to generate the organoids (see title, abstract, and page 2). Regarding claims 46, 60 and 64, Hisha teaches the culture system beneficially includes noggin (reads on BMP inhibitor and TGF-beta inhibitor) (see pages 2 and 7).
It would have been obvious to combine Nigam and to include Hisha’s noggin in Nigam’s medium. A person of ordinary skill in the art would have had a reasonable expectation of success in including Hisha’s noggin in Nigam’s medium, because Hisha teaches this media additive epithelial stem cell organoids. The skilled artisan would have been motivated to include Hisha’s noggin in Nigam’s medium because both references teach cell culture medium for epithelial stem/progenitor cells that form organoid structures and Hisha teaches this media additive epithelial stem cell culture to form such organoids.
As stated above, Nigam teaches including neuregulin, which is the same “ErbB3/4 ligand” as is in the claimed composition (as claimed in dependent claim 58). Additionally, the instant specification identifies neuregulin as having the functional property of being able to induce the heterodimerization of ErbB3 or ErbB4 with ErbB2. Therefore, regarding the functional limitation of independent claim 46 wherein the “ErbB3/4 ligand induces the heterodimerization of ErbB3 or ErbB4 with ErbB2”, since Nigam teaches the same ErbB3/4 ligand, Nigam’s neuregulin reads on having this functional property. Similarly, since Nigam teaches including FGF7 & FGF10, which are the same FGFR2b ligands as are in the claimed composition (claim 59), and Hisha teaches noggin which is the same BMP inhibitor as is in the claimed composition (claim 61), Nigam’s FGF7 & FGF10 and Hisha’s noggin read on having the functional properties of “elicits tyrosine phosphorylation of FRS2α or FRS2β” and “binds to a BMP molecule to form a complex wherein the BMP activity is neutralized”. It is also noted that the instant specification identifies FGF7, FGF10 and noggin as having these functional properties.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 11/4/2025 have been fully considered but they are not persuasive.
Applicant argues the recitation “tissue specific” overcomes the rejection.
The instant specification is noted for claim interpretation. The instant specification used the phrase “tissue-specific” on page 41 and 74.
As discussed in the rejection above, both Sato and Nigam teach organoids with tissue specific functions. Note Sato teaches : The invention further relates to a cell culture medium comprising a BMP inhibitor, a mitogenic growth factor, and a Wnt agonist, to the use of the culture medium, and to crypt-villus organoids, gastric organoids, pancreatic organoids, liver organoids, colon organoids, Barrett's Esophagus organoids, adenocarcinoma organoids and colon carcinoma organoids that are formed in the culture medium. The only teaching missing is ErbB3/4 ligand. Nigam identifies ErbB3/4 ligand is being beneficial for growth and survival of cells in organoids in paragraph [0009] and also teaches cell compositions to produce tissue specific organoids including breast, salivary, pancreatic, biliary tissue.
Applicant does not argue the merits of Sato. Applicant argues Nigam does not teach ErbB3/4 ligand as claimed. Applicant argues Nigam describes a 2 step process and argue the process in which Nigam tissue specific mesenchyme is made. Applicant argues the instant invention is a one step process. Applicant argues that Hisha does not cure the deficiencies of Nigam. The arguments pertaining to Nigam have been addressed.
This argument is not persuasive since applicant’s claims are directed to a product, a tissue-specific organoid in a culture medium, and not a method of making. The rejection of Sato in view of Nigam is based on the motivation to add the specific component (ErbB3/4 ligand) to the culture medium. The rejection of Nigam in view of Hisha is based on the motivation to use adult epithelial stems cell as the stem cells and noggin. Applicant arguments pertain to the method of making and not the product itself. The fact that Nigam teaches a two-process step does not negate the fact that there is a motivation to add ErbB3/4 ligand to Sato’s medium. The fact that Nigam teaches a two process step does not negate Nigam teaches of a tissue-specific product with a culture medium comprising all components except for noggin (the motivation of adding noggin is from Hisha which is not argued). Thus, the arguments are unpersuasive and the rejections are maintained.
Conclusion
No claims are free of the art. No claims are 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.
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/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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