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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/02/2026 has been entered.
Status of the Claims
Claims 11-13, 19, 35, 37, 39, and 41-50 are currently pending.
Claims 19, 37, and 47 are amended.
Claims 1-10, 14-18, 20-34, 36, 38, and 40 are cancelled.
New claims 48-50 have been added.
Claims 11-13, 19, 35, 37, 39, and 41-50 have been considered on the merits.
Withdrawn Rejections
The 35 U.S.C. 112(a) written description rejections made onto claim 19, and its dependents, are withdrawn in light of the amendments and arguments submitted on 03/02/2026.
The 35 U.S.C. 112(b) rejections made onto claim 19, and its dependents, are withdrawn in light of the amendments submitted on 03/02/2026.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 11-13, 19, 35, 37, 39, and 41-50 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claims do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
The claims
The claims are directed to:
a cell structure comprising fibrin, a fragmented exogenous collagen component that comprises type 1 collagen, wherein the amount of the fragmented extracellular matrix component is 1.4 mg or more and 2.3 mg or less per 1.0 x 10^6 cells, a population of cells including adipocytes that are capable of being induced to differentiate, an intercellular vascular network of blood vessel branches that extend among the cells and surround the cells, and wherein the cell structure is configured to not adhere to a support.
The claims are directed to a composition of a nature-based product, i.e., the cell structure as a whole contains fibrin, collagen comprising type 1 collagen, a cell population including adipocytes, an intercellular vascular network of blood vessels, and no support structure; all of which are characteristics of naturally occurring adipose tissue. This nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. In this regard, the disclosed cells and extracellular matrix exist entirely in nature (e.g., same genotype and phenotype potential and structure).
The claims contain the term “fragmented exogenous collagen”. Exogenous collagen in the prior art typically refers to synthetic or artificially produced collagen; however the instant specification provides an explicit definition at para [0042]. The specification states that:
“The "exogenous extracellular matrix component" refers to an extracellular matrix component supplied from the external. The cell structure according to the present embodiment comprises a fragmented extracellular matrix component as an exogenous extracellular matrix component. The animal species as the origin of the exogenous extracellular matrix component may be identical to or different from the animal species as the origin of the endogenous extracellular matrix component. Examples of the animal species as the origin include humans, pigs, and bovines. The exogenous extracellular matrix component may be an artificial extracellular matrix component.” (para [0042]).
Therefore, the specification defines exogenous as being supplemented from outside the body only, and the claims read on naturally occurring human collagen which has been taken from a body and “supplied from the external” to the cell structure as required by the definition of [0042].
The art, Spencer et al (J Clin Endocrinol Metab, 2011), teaches about adipose tissue extracellular matrix and vascular abnormalities in the naturally occurring adipose tissue of obese and/or insulin resistant patients (abstract). Spencer teaches that naturally occurring adipose tissue contains type 1 collagen (pg. E1993, Col. 2, para 2). Spencer teaches that naturally occurring adipose tissue contains a cell population including adipocytes, endothelial cells, and stromal cells (also known as mesenchymal stem cells; which are inherently capable of differentiation) (pg. E1991, col. 1, para 2). Spencer also teaches that naturally occurring adipose tissue is vascularized (pg. E1991, col. 2, para 2) and that the vascularization is seen in both fibrotic and nonfibrotic tissue areas (pg. E1992, Col. 1, para 5). Although Spencer does not describe the fibrin content of the fibrotic tissue, Paton et al (FASEB Journal, 2013, abstract) also characterizes adipose tissue of obese patient origin and states “Fibrinogen expression and deposition is increased with obesity. The increase in fibrinogen expression and fibrin deposition leads to increased adipocyte inflammation and macrophage infiltration which suppresses glucose uptake and may promote adipose tissue fibrosis” (abstract). Therefore, Spencer and Paton demonstrate that the required components of the claim amount to no more than naturally occurring adipose tissue.
Additionally, the claim requires “wherein the amount of the fragmented extracellular matrix component is 1.4 mg or more and 2.3 mg or less per 1.0 x 10^6 cells”. This limitations does not appear to impart a markedly different characteristic to the claimed cell construct than that of naturally occurring adipose tissue due to no limitation of the size of the cell construct meant to incorporate 1.4-2.3 mg per 1 x 10^6 cells. Individual adipocytes can range in size from 20 µm to over 200 µm, due to variability in fat storage. A 1 mm3 piece of adipose tissue can contain around 60,000-100,000 ~20 µm diameter adipose cells or around 90-125 ~200 µm diameter adipose cells. Additionally, a 1 mm3 piece of adipose tissue can contain anywhere from 5-10% dry weight of extracellular matrix components, assuming a 1 mm3 piece of adipose tissue weighs about 1 mg, this would amount to between 0.05-0.1 mg dry weight of extracellular matrix per 1 mm3 of adipose tissue. Based on this, a 30 mg or mm3 sample of naturally derived adipose tissue would contain about 1.5-3 mg dry weight of extracellular matrix components. Further depending on the size of the adipocytes, the 30 mg or mm3 sample of naturally derived adipose tissue could contain anywhere from a minimum of 2850 cells (of ~200 µm diameter) to a maximum of 3 x 10^6 cells (of ~20 µm diameter). It is understood that not all cells in an adipose tissue sample will be identical in size and therefore the naturally occurring tissue would have a range of adipocyte sizes. However, this calculation is meant to demonstrate that adipocytes have a natural variation of size amounting to a natural variation in extracellular matrix component concentration per number of cells in any given area and it is well within the bounds of a natural tissue to contain about 1.4-2.3 mg of extracellular matrix components per 1.0 x 10^6 cells. Thus, this claim phrase does not amount to a markedly different characteristic than naturally occurring adipose tissue.
Additionally, the dependent claim 50 requires ”an average number of blood vessel branches between 2.5-4.5” which is a feature of naturally occurring biological tissues as described explicitly by the instant specification at para [0023]: “If the average value of the number of vascular branches in the cell structure is 2.5 or more and 4.5 or less or 3.0 or more and 4.2 or less, for example, the number of vascular branches in the cell structure may be determined to be similar to the number of vascular branches in biological tissues”. Therefore, the specification supports that the claimed limitation regarding the number of blood vessel branches is a feature of a naturally occurring biological tissue.
The dependent claim 48 also require blood vessels having a diameter of more than 0 μm and less than 25 μm which account for 60% or more of the total blood vessel diameter, which is also a feature of naturally occurring biological tissue as described explicitly by the instant specification at para [0023]: “If 60% or more, 70% or more, or 80% or more of all of the vascular diameters are distributed within more than 0 pm and less than 25 μm, for example, determination may be made as having diversity of vascular diameter similar to that in biological tissues”. Therefore, the specification supports that the claimed limitation regarding the diameter of blood vessel branches is a feature of a naturally occurring biological tissue.
The claims thus encompass cells, fibrin, collagen, and vascularization that are identical (no difference in characteristics) to the naturally occurring adipose tissue in the body. Because there is no difference between the cells, fibrin, collagen, and vascularization in the claim and naturally occurring adipose tissue containing the adipocytes, fibrin, collagen, and vascularization, the cell structure of claim 19 does not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed invention is directed to an exception. Because the claimed invention does not include any additional features that could add significantly more to the exception, the claimed culture does not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
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An examination of Step 2A in the revised 101 guidance, with respect to the claimed invention, the answer is yes since the claimed invention comprises naturally occurring products (judicial exceptions), in the instant case these naturally occurring products are the adipocytes, fibrin, collagen, and vascularization. When examining the claimed invention with regards to Step 2A prong 1, the answer is yes since the claimed invention comprises naturally occurring products. When examining the claimed invention with regards to Step 2A prong 2, the answer is no since the claimed invention does not integrate the judicial exception, in the instant case the cell structure containing adipocytes, fibrin, collagen, and vascularization, into a practical application.
It is only the recited limitations in the claims that are examined under 101 and not aspects such as what the cell structure are capable of treating or used for (i.e. adipose cell construct for transplantation). In this case only the adipocytes, fibrin, collagen, and vascularization of the cell construct are examined with respect to their status as judicial exceptions. It is again emphasized that the claimed invention is a composition and not a method.
An examination of Step 2B, the answer is no with respect to the claimed invention. There are no other additional elements recited in the claim that would amount to significantly more than the judicial exceptions. The adipocytes, fibrin, collagen, and vascularization of the cell construct as claimed are indistinguishable from those that exist in nature and there are no limitations that add any additional elements to the claimed cell structure containing adipocytes, fibrin, collagen, and vascularization. The cell structure has the same function as they do in nature and the fact that they may exist in an isolated system, and in a cell structure form, does not change the cell structure in significant or meaningful way to amount to more than the judicial exception.
The only factors which can be examined under 101 in the claimed composition are those that are recited in the claim i.e. cell structure containing adipocytes, fibrin, collagen, and vascularization. How the cells or ECM were obtained and the knowledge of using them are not considered with respect to a composition claim, it is only the judicial exceptions themselves that are analyzed under 101 and in this case all of the components in the claimed composition are naturally-occurring products and thus qualifies as a judicial exception.
Additionally, the dependent claims do not include limitations which amount to more than the naturally occurring product. Claims 11, 13, 35, 37, 43, 44, and 47 contain limitations which further describe the naturally occurring cells which have already been addressed above as being taught in the art as naturally occurring products of nature. Claims 12, 39, 41, 42, 45-46, and 49 recite limitations which further describe the collagen, its naturally occurring components, as well as the method by which the collagen is obtained, which have been addressed above by the collagen being a naturally occurring product and that the method by which the collagen is obtained not being considered with respect to composition. Therefore, claims 11-13, 19, 35, 37, 39, and 41-50 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
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 11-15, 19, and 34-44 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 19 recites the limitation "the fragmented extracellular matrix component" in line 5 of claim 19. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the support" in the last line of the claim. There is insufficient antecedent basis for this limitation in the claim.
Claim 19, and its dependents, remain rejected for being indefinite for reciting the phrase “the artificially constructed cell structure is a cell aggregate configured to not adhere to the support” in the last two lines of the claim. This phrase implies that a step must occur to meet the limitation. However, no steps are recited making the claim indefinite in scope. Additionally, it is unclear how one might “configure” a cell to not adhere to a support. Typically, supports such as culture vessels, are what one would “configure” to not allow cells to adhere. For example, culture surfaces are routinely coated or passivated with specialized materials to create a barrier between the culture vessel and the cells, which does not allow for the cells to adhere. However, this does not amount to the cells themselves being altered such that they no longer adhere. The specification does not clarify how one might “configure” the cell to not adhere to a culture vessel or support. The specification does appear to describe that the fragmented extracellular matrix contacts the cells and the cells themselves are not in contact with the support. In this case, the fragmented extracellular matrix is the coating which is applied to the support vessel. Thus, it is unclear how the cells are “configured to not adhere to the support”. Appropriate clarification is required.
Claim 19 recites the phrase “a population of cells that include adipocytes that are capable of being induced to differentiate” in lines 8-9, which is indefinite. It is unclear whether the phrase “that are capable of being induced to differentiate” is meant to apply to the cell population as a whole or specifically the adipocytes included in the population. If the phrase is meant to limit the adipocytes, it is further unclear how a terminally differentiated cell, an adipocyte, is capable of differentiation. In the alternative, if the phrase “that are capable of being induced to differentiate” is meant to apply to the cell population as a whole, which includes adipocytes, it remains unclear how adipocytes are able to further differentiate. Appropriate clarification is required.
Claim Rejections - 35 USC § 112
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 12 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 12 recites “wherein an amount of the fragmented exogenous collagen component is 0.1 to 100 mg per 1.0 x 10^6 cells”, however independent claim 19 has been amended to include the limitation “ wherein the amount of the fragmented extracellular matrix component is 1.4 mg or more and 2.3 mg or less per 1.0 x 10^6 cells”. The term “fragmented extracellular matrix component” lacks antecedent basis (as described in the 112(b) rejections above) but appears to be referring to the “fragmented exogenous collagen component that comprises a type 1 collagen” which would render the limitations of claim 12 broader because claim 19 limits the amount of fragmented exogenous collagen component to between 1.4-2.3 mg per 1.0 x 10^6 cells and claim 12 limits to an amount between 0.1-100 mg per 1.0 x 10^6 cells, which is a larger range than the independent claim. Thus, claim 12 claims a larger range than the independent claim 19, thereby failing to further limit claim 19. The limitation would render the In the alternative, if Applicants intended the term “fragmented extracellular matrix component” to mean both the fibrin and collagen, claim 12 would still amount to a broader limitation than recited in claim 19, thereby failing to further limit claim 19. Additionally, this secondary interpretation of “fragmented extracellular matrix component” does not appear to be what applicant intended because the fibrin of the claim is not claimed as “fragmented”. 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 Interpretation
Claim 19 contains the phrase “exogenous collagen”. The specification teaches that “The ‘exogenous extracellular matrix component’ refers to an extracellular matrix component supplied from the external… [t]he animal species as the origin of the exogenous extracellular matrix component may be identical to or different from the animal species as the origin of the endogenous extracellular matrix component. Therefore, the term “exogenous collagen” is being interpreted to mean any collagen which is introduced from outside the body, regardless of the body/species or origin of the collagen itself.
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.
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.
Claims 11-13, 19, 35, 37, 39, and 41-50 are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al (Journal of Controlled Release, 2009), as evidenced by Shoulders (Annu Rev Biochem., 2010) and as evidenced by Spencer et al (J Clin Endocrinol Metab, 2011), and in view of Irie et al (WO2018143286A1) and Verseijden et al (J Tissue Eng Regen Med, 2012); all of which are references of record.
With regards to claim 19, Choi teaches a cell structure containing a fragmented extracellular matrix component containing collagen derived from human adipose tissue (pg. 3, col 2, last para), a population of cells including adipocytes (figure 6, and abstract), and an intercellular vascular network of branched blood vessels surrounding a cell aggregate which was formed without the adhesion to a support (Fig. 4 and 6). Regarding the claim phrase “a population of cells that include adipocytes that are capable of being induced to differentiate”, Choi teaches that the human adipose derived stem cells are included in the cell population which are capable of being induced to differentiate (pg. 3, col. 2, para 2). Choi teaches that the fragmented extracellular matrix component comprises collagen (pg. 3, col 1, para 1). Choi meets the limitations of the collagen component being an “exogenous collagen” component because Choi employs collagen derived from human adipose tissue and that collagen is then used to form a cell structure in a mouse, therefore the collagen is exogenous to the mouse (pg. 3, col. 1, para 1 and see Fig. 4). Additionally, the instant specification defines “‘exogenous extracellular matrix component’ [as] refer[ing] to an extracellular matrix component supplied from the external”, therefore the collagen taught by Choi meets the limitations of claim 19.
Regarding claim 11, Choi teaches that the adipocytes in the cell structure are mature through stating that the formed structure is comparable to “fresh human adipose tissue” (pg. 6, col 1, para 2).
Regarding claim 13, Choi teaches that the population of cells comprises adipose stem cells (pg. 3, col. 2, para 2) and vascular endothelial cells, which are demonstrated through (Fig. 4 and 6) which show vascularization, thus vascular endothelial cells must be present within the blood vessels.
Choi shows that the cell structure is generally spherical in structure (Fig. 4).
Regarding claim 35, Choi teaches the cell structure contains a vascular network (Fig. 4).
Regarding claim 37, Choi teaches that the cell structure contains adipocytes, adipose stem cells, and vascular endothelial cells (Fig. 4 and pg. 3, col 1, para 3).
Regarding claim 42, Choi teaches that the fragmentation is a result of homogenization of extracellular matrix in an aqueous medium (pg. 3, col 1, para 2).
Regarding claim 43, Choi teaches that the adipose stem cells are human adipose stem cells (pg. 3, col. 2, para 2).
Regarding claim 44, Choi teaches that the cell structure contains mature human adipocytes and that the intercellular vascular network surrounds the mature adipocytes (Fig. 4 and Fig. 6).
Regarding claim 50, it appears that the cell structures of Choi meet the limitation of “an average number of blood vessel branches in the artificially constructed cell structure is between 2.5 and 4.5” as seen in Fig. 4. Fig. 4 contains images of three cell structures which each contain many blood vessels and the cell structure of mouse C contains three blood vessels which have with a thicker and larger appearance in addition to the many small blood vessels as required by claim 50.
Regarding claim 19, Choi meets the limitations of claim 19 as evidenced by Spencer. Choi provides fragmented exogenous collagen component derived directly from naturally occurring human adipose tissue (Fig. 1). Spencer teaches that naturally occurring adipose tissue contains type 1 collagen (pg. E1993, Col. 2, para 2). Thus the fragmented exogenous collagen component inherently contains type 1 collagen as required by claim 19.
Regarding claim 39, Choi meets the limitations of claim 39 as evidenced by Shoulders. Shoulders teaches that “The defining feature of collagen is an elegant structural motif in which three parallel polypeptide strands in a left-handed, polyproline II-type (PPII) helical conformation coil about each other with a one-residue stagger to form a right-handed triple helix (Figure 1)” as required by claim 39 (pg. 1 para 2).
Regarding claim 48, Choi is silent as to the percentage of blood vessels with a diameter between 0-25 μm as required by claim 48. Choi does provide images of cell structures with a vast majority of the blood vessels being very small blood vessels which likely fall within the claimed diameter range (see Fig. 4). As described in detail in the 101 rejection above, the diameter range as claimed by applicant has been taught in the instant specification to be the naturally occurring diameter range of blood vessels in biological tissues (instant specification [0023]). Additionally, the Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants' generated cell structures differ, and if so to what extent, from the cell structure of the prior art. The prior art cell structure is the same or similar because Choi does provide images of cell structures with a vast majority of the blood vessels being very small blood vessels which likely fall within the claimed diameter range (see Fig. 4). The cited art taken as a whole demonstrates a reasonable probability that the cell structures of Choi are either identical or sufficiently similar to the claimed cell structure that whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. Clear evidence that the resulting cell structure of the cited prior art does not possess a critical characteristic that is possessed by the claimed cell structure would advance prosecution and might permit allowance of claims to applicants' method for generating stem cells.
Choi does not explicitly teach that the amount of fragmented collagen is between 1.4-2.3 mg per 1 x 106 cells as required by claim 19. Choi does not explicitly teach that the amount of fragmented collagen is 0.1 to 100 mg per 1 x 106 cells as required by claim 12. Choi does not explicitly teach that the average diameter of the fragmented collagen component be 50 nm to 30 um as required by claim 41. Choi does not teach that the collagen component is derived from pigs as required by claim 45. Choi does not teach that the content ratio of the fragmented exogenous collagen component to a dry weight of the artificially constructed cell structure is 0.01% to 30% as required by claim 46. Choi does not explicitly teach that the average length of the fragmented collagen is 5 µm to 30 µm as required by claim 49.
However, Irie teaches a cell construct containing vascular endothelial cells including HUVECs (claim 5 of Irie and pg. 2, last para). Irie teaches that this cell construct contains a collagen concentration which is close to that of a living tissue and therefore is less susceptible to contraction and is more stable (pg. 3, para 2)
Regarding claims 19 and 12, the amount of fragmented collagen can be present in a range from 0.1-100 mg per 1 x 105 (i.e. 1-1000 mg per 1 x 106 cells) (pg. 5, para 8).
Regarding claim 41, Irie teaches that the average diameter of the fragmented collagen component is between 50 nm and 30 um (pg. 5, para 3).
Regarding claim 45, Irie teaches that the collagen component can be derived from pigs (pg. 5, para 1).
Regarding claim 46, Irie discloses that the content ratio of the fragmented exogenous collagen component to a dry weight of the artificially constructed cell structure is between 20-66% which overlaps with the claimed range of 0.01% to 30% as required by claim 46 (pg. 9, para 4).
Regarding claim 49, Irie teaches that the average length of the fragmented collagen is 5 µm to 30 µm (pg. 5, para 3).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the collagen-based cell construct taught by Choi as evidenced by Shoulders with the similar fragmented collagen product taught by Irie to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Irie teaches that this cell construct contains a collagen concentration which is close to that of a living tissue and therefore is less susceptible to contraction and is more stable (pg. 3, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Choi with Irie because both teach the production of cell constructs with extracellular matrix proteins which are able to yield vascularized adipose tissue.
Choi does not teach that the composition further comprises fibrin as required by claim 19, additionally, Choi and Irie meet the limitations of a cell structure containing both human adipose stem cells and umbilical vein endothelial cells, however they are both silent to the structure comprising fibrin as required by claim 43. Although Choi does teach the inclusion of stem cells as described above, Choi and Irie, do not teach that the ratio between adipose stem cells and vascular endothelial cells is between 100/1-1/100 as required by claim 13. Choi does not teach that the percentage of the vascular endothelial cell is 10% or more of a total number of cells in the population of cells as required by claim 47.
However, Verseijden teaches a composition of cell constructs containing both adipose derived mesenchymal (stromal) stem cells (ASCs) and human umbilical vein endothelial cells (HUVECs) (abstract).
Regarding claims 19 and 43, Verseijden teaches that the cell construct contains fibrin, made by adding a fibrinogen solution (pg. 171, col 1, para 2).
Regarding claim 13, Verseijden teaches that the ratio of ASCs to HUVECs is 1:1, 1:2, and/or 1:5 (abstract, pg. 170, col 2, last para).
Regarding claim 47, All of the possible ratios of ASCs to HUVECs meet the requirement of claim 47 wherein the population of vascular endothelial cells amounts to 10% or more of the total population of cells (abstract; pg. 170, col 2, last para).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the collagen-based cell construct taught by Choi and Irie with the similar fibrin-based cell construct taught by Verseijden to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Verseijden teaches that the fibrin-based constructs have pro-angiogenic influence either directly on the host vasculature or indirectly through affecting the paracrine signaling and/or interaction between ASC and HUVECS (pg. 177, para spanning col 1 and col 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Choi with Verseijden because both teach the production of cell constructs with extracellular matrix proteins which are able to yield vascularized adipose tissue.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 06/26/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks. pg. 10, last para spanning pg. 11) in reference to the prior art rejections made that Choi does not confirm differentiation and the newly added limitation of “a population of adipocytes that include adipocytes that are capable of being induced to differentiate” requires differentiation.
In response to the arguments, the arguments are not found persuasive. This phrase has been rejection under 112(b) for being indefinite. It is unclear how terminally differentiated cells, adipocytes, are capable of differentiation. It was not clear if applicant intended to mean dedifferentiation, or that the cells “capable of differentiation” are alternative cells in the claimed cell population and not meant to refer to the adipocytes. Additionally, the limitation requires only that cells be capable of differentiation, and Choi teaches the inclusion of human adipose stem cells which are inherently capable of differentiation. The “capable of” phrasing does not require that Choi test for differentiation as implied by the arguments.
Therefore the argument is not found persuasive.
Applicant argues (Remarks, pg. 11, para 2) in reference to the prior art rejections made that Choi does not disclose fibrin as a component and it would not be obvious to include fibrin. Applicant also references the Matsusaki Declaration regarding fibrin in naturally occurring adipose tissue, which will be addressed separately under the “Response to Matsusaki Declaration” below.
In response, the arguments are not found persuasive. Choi is not relied upon to teach the fibrin, rather Irie is. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11, para 3 spanning pg. 13) that the claimed cell construct provides superior properties compared to the prior art. Applicant argues the superior properties are “using CMF alone (without fibrinogen) leads to significant tissue shrinkage” and capillary formation is prevented. Applicant states “it was only under the specific conditions of 1.2% wt CMF mixed with fibrin gel that a dense vascular network was formed” and applicant states such a synergistic effect would have been highly unexpected based on the prior art.
In response, this argument is not found persuasive. Applicant’s alleged superior properties are not in commensurate in scope with the claims presented. The claims do not require the inclusion of fibrinogen, thus the arguments of “superior properties” not in commensurate in scope with the claims. Additionally, the claims do not require the specific conditions of 1.2% wt CMF mixed with fibrin gel, thus the arguments of “superior properties” not in commensurate in scope with the claims.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 13-14) in reference to the rejection made under 101 that the instant invention contains markedly different characteristics from a product of nature because of the claimed limitations including fibrin. Applicant states that fibrin is only formed temporarily at a wound site and not found in natural tissue and references the Matsusaki Declaration, regarding fibrin in naturally occurring adipose tissue, which will be addressed separately under the “Response to Matsusaki Declaration” below.
In response, the argument is not found persuasive. Although Spencer does not describe the fibrin content of the fibrotic tissue, Paton et al (FASEB Journal, 2013, abstract) also characterizes adipose tissue of obese patient origin and states “Fibrinogen expression and deposition is increased with obesity. The increase in fibrinogen expression and fibrin deposition leads to increased adipocyte inflammation and macrophage infiltration which suppresses glucose uptake and may promote adipose tissue fibrosis” (abstract). Therefore, Spencer and Paton demonstrate that the required components of the claim amount to no more than naturally occurring adipose tissue.
Therefore, the argument is not persuasive.
Response to Matsusaki Declaration
Dr. Matsusaki describes at point 5 of the declaration, that an extensive characterization of human adipose tissue-derived extracellular matrix in “the Chun article”, provided no description of fibrin. Thus, the claimed product is distinguished over a natural product.
In response, this is not found persuasive. The Chun article does describe changes in the extracellular matrix protein contents in obesity and cites to the Spencer article, reference of record in the 101 rejection above. The art, Spencer et al (J Clin Endocrinol Metab, 2011), teaches about adipose tissue extracellular matrix and vascular abnormalities in the naturally occurring adipose tissue of obese and/or insulin resistant patients (abstract). Spencer teaches that naturally occurring adipose tissue contains type 1 collagen (pg. E1993, Col. 2, para 2). Spencer teaches that naturally occurring adipose tissue contains a cell population including adipocytes, endothelial cells, and stromal cells (also known as mesenchymal stem cells; which are inherently capable of differentiation) (pg. E1991, col. 1, para 2). Spencer also teaches that naturally occurring adipose tissue is vascularized (pg. E1991, col. 2, para 2) and that the vascularization is seen in both fibrotic and nonfibrotic tissue areas (pg. E1992, Col. 1, para 5). Although Spencer does not describe the fibrin content of the fibrotic tissue, Paton et al (FASEB Journal, 2013, abstract) also characterizes adipose tissue of obese patient origin and states “Fibrinogen expression and deposition is increased with obesity. The increase in fibrinogen expression and fibrin deposition leads to increased adipocyte inflammation and macrophage infiltration which suppresses glucose uptake and may promote adipose tissue fibrosis” (abstract). Therefore, Spencer and Paton demonstrate that the required components of the claim amount to no more than naturally occurring adipose tissue in obesity.
Therefore, the argument is not found persuasive.
Dr. Matsusaki describes at point 6 of the declaration, that the office action “asserts that the population of cells including adipocytes disclosed in Choi… inherently possesses the ability to be induced to differentiate, specifically to form a vascular network. I disagree because it is not necessary and inevitable result of the prior art. Evidence from the cited Choi reference and the field of the art (Louis et al.) demonstrates that effective vascular differentiation is not an inherent property of this cell population”.
In response, this is not found persuasive. The claims do not recite “specifically to form a vascular network” and nowhere in the action was it implied that terminally differentiated adipocytes are capable of differentiating into an effective vascular network, because this is not a claimed aspect of the invention as described in this argument. Additionally, based on the presented information it appears that the “cell population” of the claim is either (i) required to be a mixed population of cells including adipocytes and stem cells wherein the only cells which are capable of differentiation are the stem cells which are not claimed in the independent claim; or (ii) the claim is claiming both the final product (fully formed cell construct already containing branched blood vessels/ a vascular network), the starting material (stem cells capable of differentiation into the final form of a vascular network), and implying process steps of differentiation of the starting material into the final product. The presented information appears to be attempting to claim a final product of a cell construct, but describe properties of the cell construct prior to it being fully formed. For example, the cell product in its final form already contains a branched blood vessel network as claimed in claim 19, thus the argument that the claimed cell population should be capable of vascular differentiation is referring to a state prior to the final formed product. Additionally, the statement “I disagree because it is not necessary and inevitable result of the prior art” appears to be refuted by Choi. Choi teaches injection of human adipose stem cells mixed with fragmented extracellular matrix components into a mouse, and the resultant cell construct contains terminally differentiated adipocytes therefore, demonstrating differentiation into adipocytes, thus the cell composition of Choi is capable of differentiation and the assertion that the cells must be capable of differentiating into a vascular network is not in commensurate in scope with the claimed cell construct.
Therefore, the argument is not found persuasive.
Dr. Matsusaki describes at point 7 that Choi provides evidence of “poor results” due to reduction in graft volume and that “although fresh adipose tissue contains mature adipocytes, Choi’s own data indicate that such tissue does not inherently exhibit sufficient regenerative capacity to prevent substantial graft volume loss”.
In response, this argument is not found persuasive. Dr. Matsusaki implies that the Choi produces a cell construct with “poor results”, however the cited portions of Choi are not referring to the production of the cell construct, rather the results of employing the produced cell construct in a transplantation. Independent claim 19 is claiming a product and not a method of transplantation, the results obtained when applying a method of use of the product are not considered to render the product claims novel. Additionally, this is not a claimed aspect of the invention.
In response to the argument regarding the differentiation capabilities of adipocytes, it is well known in the art that adipocytes are terminally differentiated cells. In the argument at point 7, the “population of cells that include adipocytes that are capable of differentiation” appears to be interpreted by Dr. Matsusaki to be a cell population of only adipocytes, where due to graft volume loss seen in the use of the cell construct, Dr. Matsusaki concludes that Choi supports that none of the terminally differentiated adipocytes are capable of differentiation. However, Choi teaches that the cell population includes human adipose stem cells and those cells are inherently capable of differentiation regardless of graft volume loss, meeting the claim limitations.
Therefore, the argument is not found persuasive.
Dr. Matsusaki states at point 8 and concludes at point 9 of the declaration that the volume reduction observed in the cell construct of Choi after the construct was employed as a graft points to the cell populations inherent inability to form a vascular network.
In response, this argument is not in commensurate in scope with the claimed cell construct. The claims recite a “population of cells that include adipocytes that are capable of differentiation”. The claims do not require that the cell construct when employed as a graft is capable of differentiation into vascular endothelial cells. Choi teaches that the cell population includes human adipose stem cells and those cells are inherently capable of differentiation regardless of graft volume loss, meeting the claim limitations.
Therefore, the argument is not found persuasive.
Dr. Matsusaki states at point 10-14 (pgs. 5-7) that the claimed range of 1.4-2.3 mg of fragmented collagen per 1.0 x10^6 cells encompass an optimized condition wherein the test examples achieved a vascular network most similar to living tissue with optimal branching and lengths.
In response, this argument is not found in commensurate in scope with the claims. While the claim recites 1.4-2.3 mg of fragmented collagen per 1.0 x 10^6 cells, this is not equated to a specific density of the collagen per million cells. For example, 1.4 mg of fragmented collagen could be suspended in 0.5 ml or in the alternative 1 ml of solution containing 1 million cells and meet the claim limitations, however the density of the 1 ml solution would be double that of the 0.5 ml solution and may not provide the results of the instant method.
Therefore, the argument is not found persuasive.
Dr. Matsusaki states at points 13 and 14 (there are two point 13 and two point 14 sections within the declaration which appears to be formatting related, this is a response to points 13 and 14 of pgs. 8-11) that the specification demonstrates that mature adipocytes are not required for the formation of the vascular network, however the specification also demonstrates that vascularization does not proceed without the inclusion of adipose derived stem cells. Dr. Matsusaki states that “the ability to form a uniform and functional vascular network is inherent to the combination of ADSCs and HUVECS within the claimed specific scaffold (fragmented collagen/fibrin). While mature adipocytes are a component of the preferred embodiment for adipose tissue regeneration, they are not a prerequisite for the successful formation of the vascular network” (pg. 11).
In response, this argument is not persuasive. This argument is not commensurate in scope with the claims because the independent claimed embodiment only requires adipocytes. This argument also appears to require that ADSCs and HUVECs be cultured together to form the cell structure. Thus it is not clear if the ADSCs and HUVECs are required to be included in the starting material, meaning these cell types are required for the process of making the cell construct, or if they are required of the final product of a cell construct as claimed. If they are meant to be included in the final product claim 19 should be amended to specify that the cell population requires ADSCs and HUVECs.
Therefore, the argument is not found persuasive.
Conclusion
No claims are allowed.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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