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 .
Claim Status
Claims 1-16 and 18 are pending.
Claims 11-16 are withdrawn.
Claims 1-10 and 18 are under examination.
Maintained Objections to Drawings
Color photographs and color drawings
The objection to the Color drawings which have been noted in this Application is maintained because the petition filed under 37 CFR 1.84(a)(2) has not yet been reviewed.
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).
Withdrawn Claim Objections
The objection to claim 2 due to informalities as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 112(a)
Written Description
The rejection of claim 7 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paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejections of claims 1-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New 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 1-10 and 18 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.
Regarding claim 1, it is unclear whether or not the BENO composition comprises the 3D culture system because the claims states “the BENO comprises a three dimensional (3D) assembly of differentiated neuronal and stromal cells from pluripotent stem cells (PSCs)” which is “embedded in a 3D cell culture system” it appears that the BENO itself is merely “embedded in” the culture system and does not comprise the 3D culture system. Reciting both that the BENO formed in the 3D culture system and calling it an “environment,” makes it unclear whether the 3D environment or cell culture system is part of the composition, and what parts of these are intended to be encompassed by the claims. The plain and ordinary meaning of “environment” is surroundings of conditions. This makes the scope of the claim unclear because the surroundings or conditions are not part of a composition.
Additionally, claim 1 recites “the BENO 3D environment,” but claim 1 does not previously recite “a BENO 3D environment,” and therefore there is improper antecedent basis for this phrase within the claim and it is unclear what “the BENO 3D environment,” is meant to encompass. Further, because the claim is a product-by process claim, it is unclear whether “the BENO 3D environment,” is intended to refer back to a step of the method of making the product or a structure of the product itself.
By nature of their ultimate dependency on claim 1, claims 2-10 and 18 are also rejected because they do not clarify the issue.
Claim Interpretation
Instant claims are drawn to a bioengineered neuronal organoid (BENO) composition “for
modeling a disease of neural tissue and/or for drug design using phenotypic tissue screening
or phenotypic drug screening” which is an intended use of the claimed BENO. Therefore, instant claims are met by a structure that otherwise meets the recited claim limitations that is capable of meeting the recited intended use.
Instant claims recite the BENO composition is “defined by a method comprising:” steps (A)-(F) (see instant claim 1), which is product-by-process language. It is noted that the Examiner has interpreted “defined by a method comprising:” to mean that the organoid is “made by a method comprising:”
Applicant is reminded that product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113) . Therefore, in the instant case, the required structure of instant claims is the organoid itself, and the recited method steps are not limiting.
Specifically, the required structure of instant product-by-process claim 1 as claimed is a neuronal organoid composition wherein the organoid comprises a three dimensional (3D) assembly of differentiated neuronal and stromal cells embedded in a 3D cell culture system, wherein the neuronal cells of the BENO are organized in a functional neuronal network, and wherein the organoid is embedded in a matrix that comprises collagen at a concentration of 0.05-50 mg/ml, wherein the BENO is embedded throughout the collagen matrix.
Additionally, due to the 112b issues discussed above, the BENO 3D environment is interpreted to be part of the method of making (the conditions or surroundings of the BENO during its method of making) and is not interpreted to be a structure of the claim.
Withdrawn Claim Rejections - 35 USC § 112(d)
The rejection of claim 7 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 as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims 1-10 under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring product without significantly more as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims 1-10 under 35 U.S.C. 102(a)(1) as being anticipated by Ackerman (National Academies Press (US); 1992. 2) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 1-10 under 35 U.S.C. 102(a)(1) as being anticipated by Preusser et al. (Brain Pathol. 2010 Apr 14;20(6):1010–1020.; henceforth “Preusser”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 1-2 and 4-10 under 35 U.S.C. 102(a)(2) as being anticipated by Quadrato et al. (WO-2017117547-A1 published 6th, July, 2017 with priority to U.S. Provisional Application No. 62/273,795 filed 31st, December, 2017 and U.S. Provisional Application No. filed 17th, November, 2016; see IDS filed 21st, August, 2023; henceforth “Quadrato”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 102
Claims 1-8 remain rejected and new claim 18 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chwalek et al. (Nat Protoc. 2015 Sep;10(9):1362-73. Epub 2015 Aug 13.; henceforth “Chwalek”).
Regarding claim 1, Chwalek discloses a bioengineered neuronal organoid (composition (“bioengineered model of 3D brain-like tissue” abstract), wherein the organoid comprises a three dimensional (3D) assembly (“3D brain-like tissue” abstract ) of differentiated neuronal (Neurons; Figures 2-3) and stromal cells (GFAP positive astrocytes Figure 3a) embedded in a 3D cell culture system (collagen embedding pg. 1362 col. 2 2nd para.; Figure 2; pg. 1368 Step 19), wherein the neuronal cells of the organoid are organized in a functional neuronal network (“Spontaneous spiking activity” Figure 3(c)), and wherein the organoid is embedded in a matrix that comprises 3 mg/mL collagen (silk-collagen protein scaffolds; abstract) (see also Figure 2) (see pg. 1368 step 19 Collagen embedding “concentration of 3 mg/ml”), wherein the BENO is embedded throughout the collagen matrix.
Regarding claim 1, although Chwalek does not disclose the organoid is “derived from pluripotent stem cells (PSCs),” this is a product-by-process limitation (see claim interpretation above). The organoid of Chwalek meets the structural limitations instant claims as described above, and it comprises the required cell types (neuronal and stromal cells), and therefore meets instant claims even though it is not derived from PSCs.
Regarding steps (A)-(F) recited in claim 1, instant claims are directed to a product which is a product-by-process, as stated above (see claim interpretation above), the organoid of Chwalek meets the structural limitations of instant claims .
Regarding the preamble of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case the organoid structure disclosed by Chwalek is capable of meeting the intended use of “modeling a disease of neural tissue and/or for drug design using phenotypic tissue screening or phenotypic drug screening” and therefore meets instant claims. Furthermore, Chwalek specifically discloses the organoid can be used for modeling a disease of neural tissue (“mechanical injury studies” and “brain-related disease models”; abstract) and for drug design screening (“drug screening tool”; abstract).
Regarding claim 1, the collagen matrix disclosed by Chwalek does not comprise Matrigel, which is a cell cultivation matrix composition extracted from Engelbreth-Holm-Swarm mouse sarcomas comprising a mixture of laminin, collagen IV, heparin sulfate proteoglycans, entactin, and growth factors.
Regarding claim 2, further to the discussion of claim 1 above, the matrix (silk-collagen protein scaffolds) comprising collagen of Chwalek forms a hydrogel structure (“hydrogels as an environment for axonal outgrowth” pg. 1363 col. 2 last para.).
Regarding claim 3, further to the discussion of claim 1 above, the organoid of Chwalek is embedded in the matrix homogeneously (see Figure 2 which shows cells that are distributed in a homogenous pattern in the “silk-collagen protein scaffold”/silk sponge).
Regarding claim 4, further to the discussion of claim 1 above, the functional neuronal
Network in the organoid of Chwalek comprises synapses (see Figure 3b which shows positive staining for SNP-25 which marks synapses and Figure 3c which evidences the organoids have spiking activity, which requires functional synapses).
Regarding claim 5, further to the discussion of claim 1 above, the functional neural network in the organoid of Chwalek comprises electrically synchronized signaling between a plurality of the neural cells (Spontaneous spiking activity that can be diminished with TTX shown in Figure 3c and Injury-triggered glutamate (Glu) release which is synchronized neurotransmitter release in response to glutamate, shown in Figure 3d).
Regarding claim 6, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), the organoid of Chwalek comprises GFAP positive astrocytes (Figure 3a) which are glial cells.
Regarding claim 7, further to the discussion of claim 1 above, the collagen matrix of Chwalek comprises collagen I (”collagen type I” pg. 1368 Step 19).
Regarding claim 8, further to the discussion of claim 1 above, the instantly claimed organoid is a product -by-process (see claim interpretation above and claim 1 rejection above), and although it can be made with step (D) of claim 1, the result of step (D) is induced neurogenesis and therefore the structure is creates it the differentiated neurons in the organoid, which are disclosed by Chwalek above (see claim 1 rejection above), the step does not impart an additional structure and is therefore met by the structure of the organoid disclosed by Chwalek above.
Regarding claim 18, further to the discussion of claim 1 above, as stated above (see claim interpretation above), the 3D environment is interpreted to be part of the method of making and does not appear to impart an additional required structure and therefore is met by the structure of the organoid disclosed by Chwalek above.
Accordingly, Chwalek anticipates instant claims.
Response to Arguments
Applicant’s arguments, filed 3rd, January, 2026, have been fully considered but are not found persuasive.
Applicant argues “the amended claims recite positive
structural features, not merely process steps, all of which must be present in any anticipating
reference, for instance:
• A collagen matrix at a concentration of 0.05-50 mg/ml;
• Serum-free cell culture medium throughout Steps (B)-(F); no serum in the final product;
• PSCs selected from induced pluripotent stem cells (iPSCs). parthenogenetic stem cells,
stem cells generated by nucleus transfer. embryonic stem cells (ESCs) and combinations
thereof;
• A matrix that does not comprise Matrigel® (a cell cultivation matrix composition
extracted from Engelbreth-Holm-Swarm mouse sarcomas comprising a mixture of
laminin, collagen IV, heparin sulfate proteoglycans, entactin, and growth factors); and
• A BENO that is embedded in the collagen-based extracellular matrix in the 3D cell
culture system (pg. 19-20).
In response, as stated above, and as acknowledged by Applicant (remarks pg. 19), instant claims are product-by process claims. As set forth above, product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113).
Regarding Applicant’s arguments concerning specific structural features, these are met by Chwalek for the following reasons:
Regarding the collagen matrix, Chwalek discloses embedding in a collagen I matrix that comprises 3 mg/mL collagen (silk-collagen protein scaffolds; abstract) (see also Figure 2) (see pg. 1368 step 19 Collagen embedding “concentration of 3 mg/ml”), and therefore meets the structural limitation.
Regarding the serum free culture medium, as currently claimed, this is not a structural requirement under the broadest reasonable interpretation of instant claims. Specifically, instant claims recite “the PSCs are embedded in a collagen matrix at a concentration of 0.05-50 mg/ml in serum-free cell-culture medium to form a 3D culture.” This step alone does not require the alleged structure of “no serum in the final product.” Specifically, instant claims are drawn to where the BENO is formed “by a method comprising.” The transitional phrase “comprising” is open ended and does not exclude additional steps or elements. Therefore, the broadest reasonable interpretation includes other method steps or components that may have serum and does not require a serum-free final product. Furthermore, the structure of the BENO itself is the cells embedded in the collagen matrix, where the cell culture medium is not a part of the BENO composition as currently claimed.
Regarding the “PSCs selected from induced pluripotent stem cells (iPSCs), parthenogenetic stem cells, stem cells generated by nucleus transfer embryonic stem cells (ESCs) and combinations thereof,” this does not impart an additional structure because the PSCs are not part of the final BENO composition, which only requires cells of neuronal and stromal cells. There is nothing instant claims that excludes neuronal an stromal cells that are not made from PSCs because they are structurally indistinguishable.
Regarding the matrix that does not comprise Matrigel® (a cell cultivation matrix composition extracted from Engelbreth-Holm-Swarm mouse sarcomas comprising a mixture of laminin, collagen IV, heparin sulfate proteoglycans, entactin, and growth factors), the matrix of Chwalek is a collagen I matrix that does not comprise Matrigel.
Regarding the BENO that is embedded in the collagen-based extracellular matrix in the 3D cell culture system, this is disclosed by Chwalek for the reasons set forth above.
Applicant argues “the claimed staged differentiation protocol (Steps C-F) using defined
exogenous small molecule inhibitors produce a BENO embedded in a 3D collagen-rich matrix
featuring neuronal and glial cell populations, cortical layer organization, and functional
network properties that differ from naturally occurring brain tissue or prior art organoids
produced by different methods, as detailed above.” (pg. 20).
In response, the organoid disclosed by Chwalek meets the structural limitations of instant claims or the reasons stated above, Applicant had not provided data or factually objective evidence on the record concerning the actual structural differences of the BENO composition as claimed.
Applicant specifically argues the Chwalek reference (pg. 26-27). Applicant argues the following:
“1. Chwalek Uses Primary Rat Cortical Neurons-Not PSCs” (pg. 26)
In response, as discussed above, structure because the PSCs are not part of the final BENO composition, which only requires cells of neuronal and stromal cells. There is nothing instant claims that excludes neuronal an stromal cells that are not made from PSCs because they are structurally indistinguishable.
Applicant argues “The cellular starting material and processing in Chwalek is categorically
different from that required by the claims, and thus, the result is likewise materially distinct” (pg. 26)
In response, Applicant is directed to MPEP 2145(I) which states that arguments presented by Applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In the instant case, Attorney statements that the process of making the organoid of Chwalek results in a distinct product are not evidence on their own.
Applicant argues “2. Chwalek Does Not Disclose the Staged Differentiation Protocol” (pg. 26).
Applicant argues “These steps are designed to direct the controlled proliferation and differentiation of undifferentiated PSCs into neuronal and stromal cells forming the claimed BENO and the resulting functional network. They are inapplicable to primary neurons, which are already differentiated. Applicant respectfully submits that the Examiner's product-by-process analysis cannot ignore these limitations that materially impact the structure of the claimed BENO. Further, there does not appear to be any evidence showing that the product of Chwalek is exactly the same as the product presently claimed.”
In response, the organoid disclosed by Chwalek meets the structural limitations of instant claims or the reasons stated above, Applicant had not provided data or factually objective evidence on the record concerning the actual structural differences of the BENO composition as claimed. As stated above, arguments presented by Applicant cannot take the place of evidence in the record (MPEP 2145(I)) and Attorney statements that the process of making the organoid of Chwalek results in a distinct product are not evidence.
Applicant argues “there does not appear to be any evidence showing that the product of Chwalek is exactly the same as the product presently claimed” (pg. 26).
In response, the organoid disclosed by Chwalek meets the structural limitations of instant claims or the reasons stated above,
Applicant is directed to MPEP 2113 (I) which cites In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). In the instant case, the organoid disclosed by Chwalek meets the broadest reasonable interpretation of the structure of instant claims for the reasons stated above because the end product, the organoid, comprises a bioengineered neuronal organoid (composition (“bioengineered model of 3D brain-like tissue” abstract), wherein the organoid comprises a three dimensional (3D) assembly (“3D brain-like tissue” abstract ) of differentiated neuronal (Neurons; Figures 2-3) and stromal cells (GFAP positive astrocytes Figure 3a) embedded in a 3D cell culture system (collagen embedding pg. 1362 col. 2 2nd para.; Figure 2; pg. 1368 Step 19), wherein the neuronal cells of the organoid are organized in a functional neuronal network (“Spontaneous spiking activity” Figure 3(c)), and wherein the organoid is embedded in a matrix that comprises 3 mg/mL collagen (silk-collagen protein scaffolds; abstract) (see also Figure 2) (see pg. 1368 step 19 Collagen embedding “concentration of 3 mg/ml”), wherein the BENO is embedded throughout the collagen matrix.
Applicant argues “3. Chwalek Uses a Silk-Collagen Composite Scaffold-Not a Collagen Matrix” (pg. 27).
In response, Chwalek meets instant claims because the Silk-Collagen Composite Scaffold disclosed by Chwalek comprises collagen matrix in the claimed concentration range. Applicant’s claim does not exclude Silk.
Applicant argues “4. Chwalek Uses Serum-Containing Medium”(pg. 27).
In response, as discussed above, the serum-free cultured media does not impart a structure on the organoid composition as claimed.
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.
Claims 9-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Chwalek et al. (Nat Protoc. 2015 Sep;10(9):1362-73. Epub 2015 Aug 13.; henceforth “Chwalek”) in view of Quadrato et al. (WO-2017117547-A1 published 6th, July, 2017 with priority to U.S. Provisional Application No. 62/273,795 filed 31st, December, 2017 and U.S. Provisional Application No. filed 17th, November, 2016; see IDS filed 21st, August, 2023; henceforth “Quadrato”).
The teachings of Chwalek above are relied upon and are hereby incorporated in their entirety.
Regarding claims 9-10, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above and claim interpretation above), instant claims are directed to a product-by-process. As discussed above (see claim 1 rejection above), although Chwalek does not disclose the organoid is “derived from pluripotent stem cells (PSCs),” this is a product-by-process limitation (see claim interpretation above). The organoid of Chwalek meets the structural limitations instant claim 1 as described above, and it comprises the required cell types (neuronal and stromal cells), and therefore meets instant claims even though it is not derived from PSCs.
However, regarding claims 9-10, Chwalek does not disclose the organoid is made from human cells, which is the structure that is imparted by starting with human PSCs.
Nevertheless, regarding claims 9-10, Chwalek teaches the organoid can be adapted to be made by human patient-derived induced pluripotent stem cells (iPSCs) (instant claim 9) to develop new disease tissue models for disorders such as Alzheimer’s disease, Parkinson’s disease or epilepsy (instant claim 10) (pg. 1363 col. 1 3rd para.).
Therefore, regarding claims 9-10, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the organoid of Chwalek and simply substitute the known prior art element of the human patient-derived induced pluripotent stem cells (iPSCs) from Alzheimer’s disease, Parkinson’s disease or epilepsy patients of Chwalek for the primary cortical rat neurons of Chwalek to obtain the predictable result of a neural organoid comprising human cells. One of ordinary skill would have been motivated to do so as taught by Chwalek to develop new disease tissue models for disorders such as Alzheimer’s disease, Parkinson’s disease or epilepsy (instant claim 10) (pg. 1363 col. 1 3rd para.). Regarding the reasonable expectation of success, Quadrato evidences preparation of a neural organoid using human PSCs (abstract; pg. 69 last para. and pg. 70 1st para.)
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 3rd, January, 2026, have been fully considered but are not found persuasive.
Applicant argues “The claimed staged differentiation protocol (Steps C-F) using
defined small molecule inhibitors (ROCKi, SMAD inhibitors, TGF-beta, notch inhibitors) in a
Matrigel-free, serum-free, collagen-based system necessarily produce an organoid with
structural and functional characteristics that are distinguishable and nonobvious from the
products of either Chwalek or Quadrato.” (pg. 29). Applicant argues “even if Chwalek and Quadrato were combined as proposed, the combination would still fail to teach or suggest several limitations of amended Claim 1”
In response, this is discussed in the response to rejection under 35 U.S.C. 102 above. Chwalek discloses all the required limitations of the instant claims for the reasons stated above.
Applicant argues “Neither Reference Teaches a Matrigel-Free Collagen Matrix” (pg. 30).
In response, the reference of Chwalek discloses all the required limitations of the instant claims for the reasons stated above. Specifically, the silk-collagen composite of Chwalek meets the instantly claimed limitations for the reasons stated above.
Applicant argues “Neither Reference Teaches the Claimed Staged Differentiation Protocol” (pg. 30).
In response, as discussed above, the staged differentiation protocol is not required to be taught because instant claims are product-by process claims. The reference of Chwalek discloses all the required limitations of the instant claims for the reasons stated above, and suggests the substitution for human cells. Quadrato is relied upon only to additionally help demonstrate a reasonable expectation of success, as discussed above.
Applicant argues “Neither Reference Teaches Serum-Free Culture Throughout All Steps” (pg. 30).
In response, as discussed above, the specific steps are not required to be taught because instant claims are product-by process claims. Furthermore, serum free medium is not part of the composition for the reasons stated above, and because the instant claims are open to including other elements, serum is not entirely precluded from the organoid or the method of making the organoid composition.
Applicant argues “No Motivation to Combine the References as Proposed” (pg. 30). Applicant argues “Primary Neurons and PSCs Are Fundamentally Different Starting Materials” (pg. 30) and “Substituting PSCs for primary neurons is not a simple substitution, this requires an entirely different experimental paradigm. For instance, a POSITA would understand that: • Primary neurons can be directly seeded into a scaffold and will form networks based on their intrinsic neuronal identity; and • PSCs must first be induced to become neural progenitors, then differentiated into neurons and glia through carefully timed factor treatments, which leads to different densities and proliferation patterns. The Examiner's suggestion that Chwalek teaches the protocol "can be adapted" to human iPSCs does not provide the specific differentiation protocol required to accomplish this adaptation to create the structure of the claimed BENOs. The POSITA would have to materially modify Chwalek at least by completely abandoning the starting cell material, primary rat cortical neurons, in favor of PSCs, which must be matured according to some undisclosed protocol.” (pg. 32).
In response, as stated above, Chwalek specifically teaches the organoid can be adapted to be made by human patient-derived induced pluripotent stem cells (iPSCs) to develop new disease tissue models for disorders such as Alzheimer’s disease, Parkinson’s disease or epilepsy (instant claim 10) (pg. 1363 col. 1 3rd para.). Although Chwalek does not disclose a specific protocol for obtaining cortical neurons from iPSCs, many protocols for obtaining cortical neurons from human iPSCs, are known in the art, and the suggested combination would merely require a person of ordinary skill to perform any one of these known protocols to obtain neurons for use in the method of to obtain the organoid composition. Specifically, a person of ordinary skill would be able to take the suggested iPSCs of Chwalek, differentiate them into neurons with known protocols, and seed them into the suggested matrix of Chwalek with a reasonable expectation of success. Importantly, in order to complete the art of record and rebut Applicant’s arguments, Applicant is directed to the art of Handel et al. (Hum Mol Genet. 2016 Jan 5;25(5):989–1000.; henceforth “Handel”) which evidences one such known protocol that could be used to make cortical neurons from iPSCs (pg. 997 col. 1 “Cortical neuronal differentiation”). Applicant is directed to MPEP 2141.03 (I) which states that "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. In the instant case, a person of ordinary skill would employ creative steps to combine well-known differentiation protocols, such as but not necessarily limited to the protocol of Handel, in order to fit the teachings of Chwalek together to make the suggested organoid composition the human cells as suggested above with a reasonable expectation of success.
Applicant argues “Chwalek's passing statement about future adaptability is not an enabling teaching of how to actually achieve functional organoids from PSCs” (pg. 32).
In response, while the cited statement alone does not provide all the information for reasonable expectation of success, one of ordinary skill would have a reasonable expectation of success in making the suggested organoid because methods of obtaining human cortical neurons from iPSCS are known in the art, and the substitution would merely require using one of these known methods to make human cortical neurons and using them instead of the rat neurons in the method of Chwalek. Furthermore, the prior art reference of Quadrato is cited to show that there is a reasonable expectation of success in obtaining organoids while using human cells.
Furthermore, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). In the instant case, there is a reasonable expectation of success because Chwalek evidences the protocol with rat neurons and one of ordinary skill would be able to make human neurons from human iPSCS with known protocols and reasonably expect them to work in the method of Chwalek. This is further evidence by the art of Quadrato which evidences that human cells can be used to make neural organoid compositions.
Applicant argues “Quadrato 's Matrigel-Based Protocol ls Incompatible with Chwalek's Collagen
Scaffold” (pg. 32).
In response, the rejection of record does not suggest combining the Matrigel-Based Protocol with the Collagen Scaffold and therefore this is not found persuasive. Quadrato is merely cited to additionally evidence a reasonable expectation of success, which is discussed above.
Applicant argues no Reasonable Expectation of Success (pg. 33-34). Specifically, Applicant argues “The Claimed Protocol Was Not Predictable from the Prior Art” (pg. 33-34).
In response, as discussed above, it is the organoid composition which is currently claimed as a product-by process, and therefore whether the protocol itself was predictable is not pertinent rejections of record. The structures organoid composition suggested by Chwalek in view of Quadrato is made obvious for the reasons discussed above. Furthermore, because Chwalek is able to obtain an organoid with rat neurons, one of ordinary skill would have been able to be able to predictably obtain an organoid with the required structure from human neurons from human iPSCs for the reasons stated above.
Applicant argues “Prior Art Taught That Matrigel Was Necessary for Neurogenesis” (pg. 34).
In response, as discussed above, it is the organoid composition which is currently claimed as a product-by process, and therefore whether the protocol was predictable is not pertinent rejections of record. The structures organoid composition suggested by Chwalek in view of Quadrato is made obvious for the reasons discussed above. Furthermore, as discussed above, the protocol of Chwalek does not use Matrigel and therefore meets these requirements.
Applicant argues “The Combination of TGF-beta and Notch Inhibition Produced Unexpected
Results” (pg. 34). Applicant argues “This synergistic outcome-concurrent development of neurons and glia in a functional network-was unexpected “ (pg. 34).
In response, as discussed above, Chwalek teaches a functional neuronal network (“Spontaneous spiking activity” Figure 3(c)) and therefore this result does not appear to be unexpected.
Further, In response to Applicant’s arguments, arguments of counsel cannot take the place of
factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145
USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed.
Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus,
Attorney statements regarding the unexpected result (i.e., “a level of network function not achieved in prior art organoids” pg. 34) are not evidence without a supporting declaration. Specifically, Applicant
has not provided objective scientific evidence on the record that the level of network function is not achieved in prior art organoids. Additionally, instant claims only require the structure of a functional neuronal network and do not require a specific level of activity or function.
Applicant is directed to MPEP 716.02(b) which states that the burden is on the Applicant to establish that results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). In the instant case, the alleged unexpected results have not been compared with the closest prior art, and therefore the statistical and practical significance of the alleged results is not apparent.
Furthermore, Applicant’s alleged unexpected results are not commensurate in scope with instant claims. Applicant cites Example 5, FIG. 10. The organoids made by the instant specification have protocol steps much more specific than instant claims including specific concentrations and timings of the claimed components (para. [000223-000243]).
Finally, Applicant is reminded that as discussed above, instant claims are drawn to a product-by process, and therefore it is the structure of the product that is under consideration. Alleged unexpected results must result in an unexpected and non-obvious structural distinction between Applicant’s product claims and the prior art to be effective.
Applicant argues “Teaching Away from Matrigel-Free Culture” (pg. 35).
In response, the recited combination merely relies upon Quadrato as additional evidence of a reasonable expectation of success, and the primary art of Chwalek does not use Matrigel.
Applicant argues “Teaching Away from the Specific Factor Combination” (pg. 35).
In response, as discussed above, it is the organoid composition which is currently claimed as a product-by process, and therefore whether the protocol was predictable is not pertinent rejections of record. The structures organoid composition suggested by Chwalek in view of Quadrato is made obvious for the reasons discussed above. Furthermore, as discussed above, the protocol of Chwalek does not use Matrigel and therefore meets these requirements.
Conclusion
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.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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