DETAILED ACTION
Applicant’s response filed January 8, 2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1-8, 10-16, and 69-81 of the claim set filed January 8, 2026 are pending. Claims 9 and 17-68 are cancelled. Claims 69-71 and 79-81 are withdrawn. Claims 1-8, 10-16, and 72-78 are being examined on the merits herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restriction
In regards to Applicant’s request for a rejoinder of claims 6-7 and dependent claims 70-71, Examiner notes Applicant amendment to claims 6 and 7 have allowed them to be rejoined and thus said claims will be examined on the merits herein. However, Examiner notes that claim 69 has been amended to depend from claim 7 and therefore, claims 69-71 are dependent on claim 7. Further, Examiner notes newly amended claim 69 and previously withdrawn claims 70-71, would have been considered a species if originally presented in the initial claim set. Applicant would have been asked to select a species of endothelial cells from claims 69-71. As such, claims 69-71 are withdrawn.
Additionally, newly submitted claims 79-81 are directed to an invention that is independent or distinct from the invention originally claimed. These inventions fail to relate to a single general inventive concept under PCT Rule 13.1 because they do not relate to one invention only, or to a group of inventions so linked so as to form a single inventive concept for the following reasons:
The originally examined claims are drawn to an at least partially recellularized isolated organ or portion thereof (i.e., a first product).
New claims 79-81 are drawn to a system for providing acute organ function to a subject in need thereof. Said claims require a connection to a patient’s circulatory system which is not required of the elected invention (i.e., a second product).
Thus, the originally examined claims (i.e., a first product) and new claims 79-81 (i.e., a second product) do not constitute a combination of categories of inventions in accordance with 37 CFR 1.475(b).
For more details regarding the groups of inventions, please refer to the Restriction/Election requirement filed May 27, 2025.
As such, claims 79-81 are withdrawn due to being directed to an invention that is independent or distinct from the invention originally elected.
Objection(s)/Rejection(s) Maintained/Updated due to Applicant Amendment
&
Response to Applicant Remarks
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.
RE: Claims 1-5, 8, 10-16, 69 and 72 are rejected under 35 U.S.C. 112(b), 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. Dependent claims 2-5, 8, 10-16, 69, and 72 are rejected by virtue of their dependency to claim 1 and for not remedying the issue at hand.
Applicant amended claim 1 to now require “wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix.” Said amendment is not sufficient to overcome the previously filed rejection and as such said rejection has been maintained and updated. Examiner notes claim 69 is now withdrawn and thus the rejection of said claim is moot.
Claims 1-8, 10-16, and 72-78 are rejected under 35 U.S.C. 112(b), 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. Dependent claims 2-5, 8, 10-16, 69, and 72 are rejected by virtue of their dependency to claim 1 and for not remedying the issue at hand.
Examiner notes the previously filed rejection stated: ‘claim 1 as currently written does not define nor specify the type of cell population, nor the amount of cells required, to be able to perform the required function of “and wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.1 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.”’ Thus, Applicant amendment has specified hepatocytes as being the cell population required to perform the required function. (Examiner further notes Applicant has amended the required function to now state “.01mmol/hr.) However, Applicant’s amendment has not clarified the amount of hepatocytes required to be able to perform the required function of “and wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.” The claim as currently written encompasses 2 hepatocyte cells. Examiner notes Applicant remarks state “ammonia clearance was increased through portal vein, hepatic vein, bile duct, and dual seeding methodologies regardless of the specific amount of cells” (p8, 1st paragraph). Examiner respectfully notes the specification teaches in Example 5 of the co-culture of endothelial cells and hepatocytes (p103). The specification teaches (Example 5, [0278]) 1x10^6 cells /ml of hepatocytes were infused to recellularize the bioengineered liver scaffolds and further teaches of measuring the ammonia clearance after seeding of the BELs with said hepatocytes (p104, 1.7, [0282]).
Thus, given the claim recites a functional limitation, it is unclear how, for example as few as 2 hepatocytes, could perform said claimed function. Thus, the claim is rendered unclear and indefinite. It is unclear if hepatocytes in any amount are able to perform the required functional limitation.
Thus, the metes and bounds of the claim cannot be reasonably ascertained and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Therefore, the claims are properly rejected.
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.
RE: Claims 1-5, 10-16, and 69 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
Applicant amended claim 1 to now require “wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix.”
Examiner notes Applicant remarks (p8, last paragraph) state that claim 1 specifies that the partially recellularized organ comprises an extracellular matrix and a population of hepatocytes that are from a different species (xenogeneic) than the ECM and as such no such construct exists in nature. However, Examiner respectfully notes both the partially recellularized organ comprising an extracellular matrix and a population of hepatocytes that are from a different species (xenogeneic) are natural products. Examiner acknowledges that the recellularized organ and the xenogeneic hepatocytes are not found together in nature. However, the specification does not provide any teaching that combining the recellularized organ and the xenogeneic hepatocytes markedly changes either of said natural products.
Thus, said amendment is not sufficient to overcome the previously filed rejection and as such said rejection has been maintained and updated. Examiner notes claim 69 is now withdrawn and thus the rejection of said claim is moot.
Claims 1-8, 10-16, and 72-78 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. All of the claims are directed to a statutory category, e.g., a composition (Step 1: YES).
The next part of the analysis involves whether the claimed invention recites or is directed to one or more judicial exceptions (Step 2A, prong one).
Claim 1: Claim 1 is directed to a biological composition comprising: “An at least partially recellularized isolated organ or portion thereof comprising an extracellular matrix and at least two different exogenous populations of cells engrafted thereon, wherein the at least partially recellularized isolated organ or portion thereof comprises an at least partially intact vasculature, and wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter, wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix.”
Examiner notes claim 1 encompasses two naturally occurring products, i.e., (1) an at least partially recellularized isolated organ or portion thereof comprising an extracellular matrix and an at least partially intact vasculature and (2) at least two different exogenous populations of cells engrafted thereon. Examiner notes said claim additionally requires “wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix.”
As noted supra, claim 1 is thus solely directed to naturally occurring products. While Examiner acknowledges that the recellularized organ and the xenogeneic hepatocytes are not found together in nature, the specification does not provide any teaching that combining the recellularized organ and the xenogeneic hepatocytes markedly changes either of said natural products. Thus, the broadest reasonable interpretation of claim 1 encompasses, for example, a mammalian liver, or portion thereof. Claim 1 encompasses, for example, a portion of a liver that has been removed from an animal. As a POSITA will appreciate, a liver has at least two different populations of cells. Examiner notes claim 1 teaches one of the populations of cells on said recellularized liver are xenogeneic hepatocytes. But as noted supra, the specification does not teach that combining the recellularized organ (i.e., a liver) and the xenogeneic hepatocytes markedly changes either of said natural products. Additionally, a dissected or “isolated” liver has an at least partially intact vasculature.
As discussed below in regards to the rejection under 35 USC 102 of claim 1, regarding the claim language and “wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.”, it is noted that this recitation is interpreted as functional language in regards to an intended use of the product and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). In addition, Examiner notes Ott (Ott, et al., Metab Brain Dis (2024) 40(1); PTO 892) evidences the liver is a net remover of ammonia, removing 0-10 micromol/min (i.e., 0-0.6 mmol/hr) in healthy persons (p6, 1st column, last paragraph). Further, and as a POSITA will appreciate, the cells of the liver responsible for said ammonia removal are hepatocytes, which Ott evidences via stating acute liver failure caused by hepatocyte necrosis allows large quantities of portal ammonia to pass and thus not be cleared (Abstract). Thus, the broadest reasonable interpretation of claim 1, to include said functional language, reads on a liver or portion thereof, seeded with xenogeneic hepatocytes performing in the same naturally occurring manner as non-xenogeneic hepatocytes, performing the naturally occurring function of a liver, i.e., ammonia removal, at the naturally occurring rate, i.e., 0-0.6 mmol/hr. To respectfully reiterate, the functional limitation of 0.01 mmol per hour appears to be a naturally occurring function of a liver.
Additionally, Examiner respectfully notes the instant specification teaches livers recellularized with hepatocytes show significant ammonia clearance. The instant specification teaches said assay confirms the ability of hepatocytes to retain their function (i.e., naturally occurring function) in high density cultures in a decellularized liver scaffold (Fig 26J, [0299]).
Thus, said functional language does not add significantly more to the claimed composition. Therefore, the claim recites a combination of natural products, i.e., an isolated organ and a population of cells (one of which is xenogeneic).
Thus, the claim as a whole, considering all claim elements both individually and in combination, does not amount to significantly more than a natural composition. There is no indication in the specification that by combining said natural products that any characteristics (structural, functional, or otherwise) are developed that are markedly different from what occurs in nature. The combination of natural products required by claim 1 does not improve or change in anyway each components natural functioning.
“To show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart. Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948).
Applicant has not shown that said functional language recitation in claim 1 is any different from what occurs in nature and is thus not an inherent characteristic of the combination of natural products. As stated in Funk Bros.: (‘‘[The inventor did] not create a state of inhibition or of non-inhibition in the bacteria. Their qualities are the work of nature. Those qualities are of course not patentable." and "… a difference in a characteristic that came about or was produced independently of any effort or influence by applicant cannot show a marked difference. Roslin, 750 F.3d at 1338 (Because ‘‘any phenotypic differences came about or were produced ‘quite independently of any effort of the patentee’’ and were ‘‘uninfluenced by Roslin’s efforts’’, they ‘‘do not confer eligibility on their claimed subject matter’’).
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claim 2, said claim recites a limitation that is considered only to be directed to functional language. This limitation does not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from its natural counterpart.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claim does not qualify as eligible subject matter and is rejected under 35 U.S.C. 101.
Regarding claims 3-5, said claims recite limitations further defining the biological composition as having blood as the circulating fluid and wherein the organ is connected to a pump. As the broadest reasonable interpretation of the claims encompasses a liver, which is known to circulate blood, and be connected to the heart, which is a natural pump, said claims do not add significantly more to the claimed composition.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claims 6-8, said claims recite naturally occurring cells. Thus, said claims are reciting products of nature.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claims 10-14, said claims recite limitations further defining the perfusion solution. However, the body naturally passages, i.e., perfuses, blood, etc. It is noted claim 11 is trying to further define through product by process language how the partial oxygen is measured, i.e., “as measured by a dissolved oxygen meter and electrode”. As such, said claim language does not add significantly more. In regards to “120 pO2 mmHg”, Examiner notes said limitation is very close to the naturally occurring partial oxygen pressure found in blood and organs and thus does not add significantly more. Claims 12-14 recite naturally occurring growth factors and immune modulating agents that are naturally found in blood. Thus, said claims are reciting products of nature.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claims 15,16, and 72, said claims recite naturally occurring cells and/or organs. Thus, said claims are reciting products of nature.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claims 73-76 and 78, said claims recite limitations that are considered only to be directed to functional language. These limitations do not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from its natural counterpart. Please see remarks above concerning said functional language in regards to claim 1.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Regarding claim 77, said claim recites naturally occurring cells and further recites a are product by process limitation directed to glucose consumption. Examiner notes a human liver naturally has a glucose consumption rate that exceeds 40 mg/h particularly in the postprandial (fed) state. Thus, this limitation does not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from its natural counterpart.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claim does not qualify as eligible subject matter and is rejected under 35 U.S.C. 101.
Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
The final part of the analysis involves whether the claimed invention, as a whole, recite something “significantly more” than the judicial exceptions (Step 2B).
In view of the above and considered as a whole, the claimed composition does not have markedly different characteristics from what occurs in nature and such elements discussed above are not significantly more than the indicated judicial exceptions. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101 (Step 2B: NO).
Thus, the claims are properly rejected.
Objection(s)/Rejection(s) Withdrawn
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
RE: Claims 1-5, 8, 10, 12-16, 69, and 72 are rejected under 35 USC 102(a)(1) and 102(a)(2) as being anticipated by Ott (US 2013/0344599 A1, published Dec. 26, 2013, earliest effective filing date August 26, 2005; IDS filed 6/14/2022). Claim 4 is rejected under 35 USC 102(a)(1) and 102(a)(2) as being anticipated by Ott as evidenced by Zimmer (Zimmer, H-G, (1998) Physiology 13(4): 203-210; PTO 892).
Applicant amended claim 1 to now require hepatocytes that are xenogeneic to the extracellular matrix. Ott does not disclose hepatocytes. As such, the previously filed rejections are withdrawn. However, Applicant’S amendment has necessitated new grounds of rejection as set forth below.
Examiner notes, as discussed supra, that claim 69 is withdrawn and thus the rejection of said claim is moot.
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.
RE: Claim 11 is rejected under 35 USC 103 as being obvious over Ott, as evidenced by Carreau (Carreau, et al., (2011) J. Cell. Mol. Med. 15(6): 1239-1253; PTO 892).
For the reasons discussed above, the anticipation rejection over Ott is withdrawn, and thus the obviousness rejection that is based on the same basis is likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection as set forth below.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plainest meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
In regards to the language of new claim 77 stating “wherein the endothelial cells are engrafted prior to the hepatocytes and the recellularized isolated organ or portion thereof is maintained until glucose consumption reaches a rate of at least 40 mg/h prior to engraftment of the hepatocytes”, Examiner notes said limitation is product by process language. Said limitation is directed to the manner by which the product, i.e., the isolated organ seeded with endothelial and hepatocyte cells is produced. Said limitation does not clearly indicate an added additional structure to the product of claim 77. Product by process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, Examiner notes the instant specification teaches it was previously reported that daily glucose consumption rates (GCR) provide a robust, non-invasive metric for monitoring cell proliferation in HUVEC-seeded bioengineered liver constructs and is predictive of successful perfusion outcomes in vivo [0297]. Examiner believes this implies the scaffold has significant endothelization. Based off this interpretation of the claim, Examiner has applied the teachings of Ross.
Thus, in the interest of compact prosecution, Examiner has cited art teaching glucose consumption rates as related to endothelization. Please see the 103 rejections of claim 77 below.
New Ground(s) of Rejection, Necessitated by Amendment
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d), 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 6 depends from claim 1. Claim 1 states “wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix.”
Claim 6 states “wherein the at least two different exogenous populations of cells engrafted thereon comprises at least one population of hepatocytes that are xenogeneic to the extracellular matrix…”
Thus, claim 6 does not further limit claim 1 as claim 1 is currently amended.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8, 10-16, and 72-78 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-8, 10-16, and 72-78 are directed to an at least partially recellularized isolated organ or portion thereof comprising an extracellular matrix and at least two different exogenous populations of cells engrafted thereon, wherein the at least partially recellularized isolated organ or portion thereof comprises an at least partially intact vasculature, and wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter, wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the extracellular matrix. Dependent claims 2-8, 10-16, and 72-78 either depend directly from claim 1 or incorporate the product of claim 1.
Upon further review of the specification, in view of the newly amended claim limitations, the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of an at least partially recellularized isolated organ or portion thereof comprising an extracellular matrix and at least two different exogenous populations of any amount of cells engrafted thereon, (i.e., this reads on 2 cells engrafted thereon) wherein the at least partially recellularized isolated organ or portion thereof comprises an at least partially intact vasculature, and wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter, wherein at least one of the exogenous populations of cells comprises hepatocytes (i.e., this reads on 1 hepatocyte) that are xenogeneic to the extracellular matrix. Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
Example 5 of the instant application (IA) teaches of the co-culture of endothelial cells and hepatocytes (p103). Example 5 of the IA teaches porcine livers were decellularized [0275] and recellularized via seeding with human umbilical vein endothelial cells (HUVECs) [0276] and porcine hepatocytes [0277]. The IA teaches 1x10^6 hepatocytes were infused in order to seed the bioengineered livers [0278]. Further, the IA teaches said bioengineered livers seeded with HUVECs and hepatocytes were analyzed for ammonia clearance and urea production [0282] in vitro [0299]. Importantly, the IA teaches livers recellularized with solely HUVECs showed a steady increase in ammonia levels over time whereas hepatocyte-only and co-culture bioengineered livers both showed significant ammonia clearance with similar kinetics although hepatocyte-only bioengineered livers showed slightly more ammonia clearance. The IA teaches said assays confirm the ability of hepatocytes to retain their function in high density cultures in a decellularized liver scaffold (Fig 26J, [0299]). Thus, the instant application teaches that 1x10^6 hepatocytes can perform the required function of ammonia clearance.
In addition, Examiner notes Barakat (cited below in regards to the 102 rejection of claim 1) teaches of the metabolic and synthetic activity of the recellularized livers and teaches glucose consumption, lactate, and urea production increased significantly during the 13-d perfusion period, indicating active metabolism within the recellularized matrices (Fig 6B-D, p17 2nd column 1st paragraph). As a POSITA will appreciate, an increase in urea production is the primary metabolic result of ammonia detoxification, i.e., ammonia clearance.
Thus, Examiner respectfully notes both Barakat and the IA teach seeding porcine livers with at least two different exogenous populations of cells and further both teach wherein one of the exogenous populations of cells comprises hepatocytes. Further, the IA teaches seeding with 1x10^6 hepatocytes and Barakat teaches seeding with at least that many hepatocytes, i.e., 1x10^9 hepatocytes. Most importantly, the IA teaches livers engineered with hepatocytes alone retain their function, i.e., ammonia clearance, in high density cultures in a decellularized liver scaffold.
The claims as currently written read on, for example, 2 hepatocytes being able to perform the required function of ammonia clearance at the specified rate. A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of, for example, 2 hepatocytes or 10 hepatocytes being able to perform the required function of ammonia clearance. Further, the prior art indicates more than 2 hepatocytes are needed for a recellularized organ to perform the required function of ammonia clearance.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 8, 10-16, 72-76 and 78 are rejected under 35 USC 102(a)(1) as being anticipated by Barakat (Barakat et al., Journal of Surgical Research (2012) 173; PTO 892). Claim 15 is rejected under 35 USC 102(a)(1) as being anticipated by Barakat as evidenced by Kordes (Kordes, et al., European Journal of Medical Research (2014) 19; PTO 892).
In regards to amended claim 1, Barakat teaches the use of decellularized porcine livers for engineering humanized liver organs. Barakat teaches of isolating porcine livers and the decellularization of said livers. Barakat further teaches wherein said livers comprised an at least partially intact vasculature, i.e., said livers comprised the portal vein and hepatic veins, as well as the supra and infrahepatic venea cavae (p12-p13, Materials and Methods, liver retrieval and liver decellularization). Barakat teaches said livers comprised decellularized matrices, i.e., an extracellular matrix (p13, 1st column, 1st paragraph). Barakat teaches of the liver matrix perfusion system and teaches of a perfusion culture system comprising units for housing, perfusion, heating, and gas mixing. Barakat teaches the flow rate of air and carbon dioxide was individually adjusted according to the gas analysis and further teaches to maintain a stable culture condition, fresh medium was infused at a rate that was adjusted according to the glucose and lactate concentrations via an extra pump in-line with the infusion pump (p13, perfusion system). Barakat teaches said livers were recellularized and teaches the livers were seeded with 3.5x10^8 human fetal stellate cells (Hfsc) and 1x10^9 human fetal hepatocytes (Hfh) (p13, recellularization procedure). Thus, Barakat teaches the isolated organs or portions thereof comprise an ECM and at least two different exogenous populations of cells engrafted thereon, wherein at least one of the exogenous populations of cells comprises hepatocytes that are xenogeneic to the ECM. I.e., Barakat teaches of porcine livers seeded with human stellate cells and human hepatocytes.
Regarding the claim language and “wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.1 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.”, it is noted that this recitation is interpreted as functional language in regards to an intended use of the claimed product and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See MPEP 2112.01 (I).
Examiner respectfully notes that Barakat teaches the same isolated organs and hepatocyte population of cells as is taught in the instant specification. Example 5 of the instant application (IA) teaches of the co-culture of endothelial cells and hepatocytes (p103). Example 5 of the IA teaches porcine livers were decellularized [0275] and recellularized via seeding with human umbilical vein endothelial cells (HUVECs) [0276] and porcine hepatocytes [0277]. The IA teaches 1x10^6 hepatocytes were infused in order to seed the bioengineered livers [0278]. Further, the IA teaches said bioengineered livers seeded with HUVECs and hepatocytes were analyzed for ammonia clearance and urea production [0282] in vitro [0299]. Importantly, the IA teaches livers recellularized with solely HUVECs showed a steady increase in ammonia levels over time whereas hepatocyte-only and co-culture bioengineered livers both showed significant ammonia clearance with similar kinetics although hepatocyte-only bioengineered livers showed slightly more ammonia clearance. The IA teaches said assays confirm the ability of hepatocytes to retain their function in high density cultures in a decellularized liver scaffold (Fig 26J, [0299]).
In addition, Examiner notes Barakat teaches of the metabolic and synthetic activity of the recellularized livers and teaches glucose consumption, lactate, and urea production increased significantly during the 13-d perfusion period, indicating active metabolism within the recellularized matrices (Fig 6B-D, p17 2nd column 1st paragraph). As a POSITA will appreciate, an increase in urea production is the primary metabolic result of ammonia detoxification, i.e., ammonia clearance.
Thus, Examiner respectfully notes both Barakat and the IA teach seeding porcine livers with at least two different exogenous populations of cells and further both teach wherein one of the exogenous populations of cells comprises hepatocytes. Further, the IA teaches seeding with 1x10^6 hepatocytes and Barakat teaches seeding with at least that many hepatocytes, i.e., 1x10^9 hepatocytes. Most importantly, the IA teaches livers engineered with hepatocytes alone retain their function, i.e., ammonia clearance, in high density cultures in a decellularized liver scaffold.
Thus, absent any evidence to the contrary, it is inherent that the recellularized isolated liver of Barakat, recellularized with at least as many hepatocytes of the IA, would clear ammonia at the claimed rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.
“Any properties exhibited by or benefits provided the composition are inherent and are not given patentable weight over the prior art. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present.” In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not inherently possess the same properties as instantly claimed product.
In regards to the claim language “exogenous populations of cell”, Examiner notes said limitation is product by process language. Said limitation is directed to the manner by which the product, i.e., the recellularized isolated organ, has been produced. The phrase “exogenous” does not add additional structure to the product of claim 1. Product by process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
Therefore, the claim is anticipated and is properly rejected.
In regards to claim 2, Barakat teaches claim 1. In regards to the claim language “wherein the at least partially intact vasculature that has a blood flow patency of at least 120 mL/min at about 15mmHg as measured by a flow meter,” it is noted that this recitation is interpreted as functional language in regards to an intended use and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Said limitation is directed to the intended use of the recellularized organ.
Additionally, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See MPEP 2112.01 (I).
Further, and as discussed supra, as Barakat and the instant application teach the same composition, absent any evidence to the contrary, it is inherent that the recellularized isolated organ comprising at least two different populations of cells engrafted thereon would necessarily have a blood flow patency of at least 120 mL/min at about 15 mmHg as measured by a flow meter.
“Any properties exhibited by or benefits provided the composition are inherent and are not given patentable weight over the prior art. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present.” In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not inherently possess the same properties as instantly claimed product.
Therefore, the claim is anticipated and is properly rejected.
In regards to claims 3, 73-76 and 78, Barakat teaches claim 1. The claim language of claim 3 states: wherein the at least partially intact vasculature comprises a circulating fluid, and wherein the at least partially recellularized isolated organ or portion thereof maintains an ammonia concentration of the circulating fluid at a level of less than about 0.4 mM in a time period of about 24 hours as measured by an ammonia analyzer.
In regards to the claim language “and wherein the at least partially recellularized isolated organ or portion thereof maintains an ammonia concentration of the circulating fluid at a level of less than about 0.4 mM in a time period of about 24 hours as measured by an ammonia analyzer,” it is noted that this recitation is interpreted as functional language related to the intended use of the product and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See MPEP 2112.01 (I).
Further, and as discussed supra, as Barakat teaches the same product as the instant application, (i.e., Barakat teaches at least as many hepatocytes seeded onto a liver which the IA teaches is required for ammonia clearance, i.e., maintaining ammonia concentration) it is inherent said product would maintain an ammonia concentration of the circulating fluid at a level of less than about 0.4 mM in a time period of about 24 hours as measured by an ammonia analyzer. “Any properties exhibited by or benefits provided the composition are inherent and are not given patentable weight over the prior art. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present.” In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not inherently possess the same properties as instantly claimed product.
In regards to the claim language wherein the at least partially intact vasculature comprises a circulating fluid, as discussed supra, Barakat teaches said product of claim 1 undergoes perfusion, i.e., comprises a circulating fluid (p13, liver matrix perfusion system).
Thus, the claim is anticipated and is properly rejected.
Examiner notes the limitations recited in claims 73-76 and 78 are directed solely to functional language in regards to the intended use of the product. Said claims functional language is directed to the rate of ammonia clearance which is discussed supra. As such, the same reasoning/logic applied to claim 3 is thus applicable to claims 73-76 and 78. For ease of reference, Examiner has listed the functional limitations required by said claims below.
Claim 73 states: wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.01 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter within 24 hours following engraftment of the at least one of the exogenous population of cells comprising the hepatocytes thereon the extracellular matrix.
Claim 74 states: wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.04 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.
Claim 75 states: wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.05 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.
Claim 76 states: wherein the at least partially recellularized isolated organ or portion thereof clears ammonia at a rate of at least 0.1 mmol per hour from a fluid perfused through the at least partially intact vasculature as measured by a flow meter.
Claim 78 states: wherein the at least partially recellularized isolated organ or portion thereof maintains an ammonia concentration of a circulating fluid at a level of less than about 0.4mM in a time period of about 24 hours.
Thus, claims 73-76 and 78 are anticipated and are properly rejected.
Examiner notes claim 78 appears to be redundant to claim 3.
In regards to claim 4, Barakat teaches claim 1. Further, Barakat teaches wherein the fluid comprises blood (Fig 4).
Thus, the claim is anticipated and is properly rejected.
In regards to claim 5, Barakat teaches claim 1. Further, Barakat teaches wherein the organ is connected to a pump (p13, liver matrix perfusion system).
Thus, the claim is anticipated and is properly rejected.
In regards to claim 6, Barakat teaches claim 1. Examiner notes claim 6 is not further limiting of amended claim 1. Please see the 112d rejection of claim 6 supra.
Thus, the claim is obvious and is properly rejected.
In regards to claim 8, Barakat teaches claim 1. Further, Barakat teaches wherein the at least two different populations of cells engrafted thereon are xenogeneic to the ECM of the organ. As discussed supra, Barakat teaches of porcine liver ECM, human fetal stellate cells and human fetal hepatocytes (Abstract).
Thus, the claim is anticipated and is properly rejected.
In regards to claim 10, Barakat teaches claim 1. Further, Barakat teaches of a perfusion solution (p13, liver matrix perfusion system).
Thus, the claim is anticipated and is properly rejected.
In regards to claim 11, Barakat teaches claim 10. In regards to the claim language reciting “as measured by a dissolved oxygen meter and electrode”, Examiner notes said limitation is product by process language. Said limitation is directed to the manner by which the product, i.e., the perfusion solution having at least 120 pO2 mmHg, is prepared. Said limitation does not add additional structure to the product of claim 11. Product by process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In regards to the limitation wherein the perfusion solution comprises at least 120 pO2 mmHg, Examiner notes Barakat teaches said limitation as is shown in Fig 6A.
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Thus, the claim is anticipated and is properly rejected.
In regards to claims 12 and 13, Barakat teaches claim 1. Further, Barakat teaches the decellularized livers were recellularized via perfusion with a hepatocyte medium and further teaches the hepatocyte medium comprised the growth factor FGF-2 (p13, human fetal liver cells and recellularization procedure).
Thus, the claims are anticipated and is properly rejected.
In regards to claim 14, Barakat teaches claim 12. Further, Barakat teaches of a perfusion solution comprising hydrocortisone, i.e., a glucocorticoid immune modulating agent (p13, human fetal liver cells).
Thus, the claim is anticipated and is properly rejected.
In regards to claims 15 and 72, Barakat teaches claim 1. Further, Barakat teaches wherein the at least 2 different exogenous populations of cells engrafted thereon further comprises human fetal stellate cells and human fetal hepatocytes, i.e., both exogenous and xenogeneic to the ECM (Abstract). As evidenced by Kordes, stellate cells represent mesenchymal stem cells (Abstract).
Thus, the claims are anticipated and is properly rejected.
In regards to claim 16, Barakat teaches claim 1. Further, Barakat teaches of recellularized liver organs (Abstract).
Thus, the claim is anticipated and is properly rejected.
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 7 and 77 are rejected under 35 USC 103 as being obvious over Barakat in view of Ross (US 2021/0322642 A1, published Oct 21, 2021, EFD June 4, 2018; PTO 892).
In regards to claims 7 and 77, Barakat teaches claim 1. Barakat does not teach of engrafting with endothelial cells.
In regards to the language of claim 77 stating “wherein the endothelial cells are engrafted prior to the hepatocytes and the recellularized isolated organ or portion thereof is maintained until glucose consumption reaches a rate of at least 40 mg/h prior to engraftment of the hepatocytes”, Examiner notes said limitation is product by process language. Said limitation is directed to the manner by which the product, i.e., the isolated organ seeded with endothelial and hepatocyte cells is produced. Said limitation does not add additional structure to the product of claim 77. Product by process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, Examiner notes the instant specification teaches it was previously reported that daily glucose consumption rates (GCR) provide a robust, non-invasive metric for monitoring cell proliferation in HUVEC-seeded bioengineered liver constructs and is predictive of successful perfusion outcomes in vivo [0297]. Examiner believes this implies the scaffold has significant endothelization. Based off this interpretation of the claim, Examiner has applied the teachings of Ross.
Ross teaches of methods of liver recellularization. Ross teaches of recellularized livers comprising an ECM and a vasculature [0004] and at least 2 different populations of cells, i.e., HUVECs (human umbilical vein endothelial cells) and hepatocytes (Example 11, [0153]). Ross further teaches the cells may be xenogeneic [0094].
The examples exemplified in Ross primarily focus on liver recellularization via HUVECs. I.e., Examples 1-10. However, Example 11 teaches of the characterization of vascular patency and ammonia clearance potential of a clinically translatable porcine liver scaffold seeded with HUVECS and primary hepatocytes [0153]. Ross teaches whole livers were decellularized to generate ECM scaffolds. Naked or HUVEC-seeded scaffolds were infused with porcine hepatocytes through the hepatic vein and cultured in bioreactors under continuous portal vein perfusion. Ross teaches of functional ammonia clearance kinetics being measured [0155].
Ross teaches co-culture grafts exhibited enhanced ammonia clearance kinetics and higher albumin production than hepatocyte only grafts. Ross teaches co - culture grafts maintained stable flow rates when perfused with blood, suggesting significant reendothelialization and the presence of a functional vasculature [0157]. Ross teaches hepatocyte function was enhanced in scaffolds seeded initially with HUVECs when compared to hepatocyte - only grafts. Co - culture grafts exhibited improved perfusion dynamics during bioreactor culture, and remained patent upon perfusion with blood. Ross teaches that taken together, these results suggest that reendothelialized porcine liver scaffold is a promising substrate for further recellularization with hepatocytes to obtain a transplantable functional liver graft to address the chronic need for transplantable livers [0158]. Ross teaches accordingly, perfusion of endothelial cells produces enhanced ammonia clearance relative to perfusion of hepatocytes alone, providing evidence that endothelialized perfusion recellularized liver are promising candidates for xenogeneic liver transplants [0159].
Further, Ross teaches of peak glucose consumption rate (PGCR) rates > 40 mg/h in bioengineered livers correlated with sustained flow rates > 50 ml / min, thereby validating the use of the PGCR as a marker for functional re -endothelialization of BELs ( n = 5 ) ( FIG . 7K).
Thus, Ross teaches of a recellularized organ (i.e., a liver) wherein at least one of the exogenous population of cells comprises endothelial cells (i.e., HUVECs) wherein the endothelial cells are engrafted prior to the hepatocytes (i.e., hepatocyte function was enhanced in scaffolds seeded initially with HUVECs) and the recellularized isolated organ or portion thereof is maintained until glucose consumption reaches a rate of at least 40 mg/h prior to engraftment of hepatocytes (i.e., peak glucose consumption rates of >40 mg/h indicated functional re-endothelialization of the bioengineered livers).
Therefore, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Barakat and Ross. As both Barakat and Ross teach of recellularized livers seeded with hepatocytes and Ross further teaches the benefits of first seeding with endothelial cells until a glucose consumption rate >40mg/h has been achieved to indicate functional re-endothelization of the livers. A POSITA would have been so motivated to combine said teachings due to Ross teaching hepatocyte function was enhanced in scaffolds seeded initially with HUVECs. A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of bioengineering.
Thus, the claims are obvious and are properly rejected.
Conclusion
No claims are allowable. No claims are free of the prior art.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633