DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 8/18/2026 to claim 4 have been entered. Claims 1-3, 7-11, 15, 21, and 24-45 are canceled. Claims 4-6, 12-14,16-20, 22, 23, and 46 remain pending, of which claims 4-6, 12-14, and 16-19 are being considered on their merits. Claims 20, 22, 23, and 46 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claim 4 have overcome the 35 U.S.C. § 112(b) rejections of record, which are withdrawn. The Declaration filed 8/18/2026 under 37 C.F.R. § 1.130(a) is sufficient to exclude Mao (of record) as available prior art. The alternative 35 U.S.C. § 102 and 103 rejections over Mao are withdrawn. In so much that US Application # 16/554,792 was abandoned on 6/25/2026, the nonstatutory double patenting rejections of record over this Application are withdrawn.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 102 and 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 4-6, 13, 14 and 16-19 remain rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Hanson et al. (U.S.PGPUB 20170369849) as evidenced by Dingle et al (2018, Angiogenesis, 21:581–597) and Sancho-Bru et al (U.S.PGPUB 20120009672).
Regarding claims 4, 6, and 13, Hanson teaches a recellularized liver comprising a rat liver extracellular biomatrix scaffold (reads on first animal being a rodent) that is decellularized by perfusion through a cannula inserted into the portal vein of the liver, and recellularized with human cells (reads on second animal being a human), such that the cells recellularize the extracellular biomatrix scaffold with cells including endothelial cells (see Examples 2 & 4 and paragraphs [0172]). Regarding claim 13, Hanson teaches that the perfusion portal vein of the liver was also used to perfuse cells for recellularization (see Example 4), and therefore combined Hanson’s teaching that perfusion was done through a cannula inserted into the portal vein of the liver, this reads on the product further comprising a cannula. Regarding claims 4-5, Hanson teaches biomatrix is a three-dimensional decellularized scaffold that retains its native three-dimensional structure, including vasculature components (see paragraphs [0047], [0102], [0118] and [0172] and Figure 1); reads on including a vasculature and non-vasculature, and substantially intact exterior surface. Regarding claim 4, Hanson teaches that the recellularized liver consumes glucose in media (see paragraphs [0026] and [0164], Figures 9A-9C).
Regarding claims 4 and 14, Hanson teaches the recellularized liver comprised sinusoidal endothelial cells expressing LYVE-1 localized to locations in the scaffold corresponding to those in vivo (see paragraph [0145] and Figure 3). Regarding claim 4, Dingle is cited solely as evidence that LYVE-1 is expressed in the parenchymal areas of the liver by sinusoidal endothelial cells (see Figure 1, especially 1b, and col. 1 on pages 588 & 596); therefore, Dingle is evidence that the endothelial cells in the parenchyma, which is most of the liver mass and reads on “parenchymal niche” express LYVE-1. Similarly, regarding claim 14, Sancho-Bru is cited solely as evidence that STAB-2 is also expressed by liver sinusoidal endothelial cells (the same cell type as discussed in Hanson and Dingle) (see paragraph [0009]). Therefore, this reads on wherein the isolated at least partially recellularized liver comprises a greater expression level of LYVE- 1 or STAB-2 in a parenchymal niche of the isolated at least partially recellularized liver relative to an expression level of LYVE- 1 or STAB-2 in a large vessel of the isolated at least partially recellularized liver as Dingle shows more parenchymal tissue than any one large vessel with expression and Sancho-Bru teaches these same cells express STAB-2.
Regarding claim 16, Hanson teaches kit comprising the recellularized liver in a container with media, Hanson exemplifies using sterile filtered media, and teaches that the recellularized liver can be used for transplantation (see Example 3, and paragraphs [0005], [0016], [0120]-[0121] and [0172]); taken together, these teachings provide for a sterile container.
Regarding claim 17, Hanson teaches the perfusion connected to the recellularized liver comprises an attached input and output, growth media, and Hanson teaches holding the cells at a specific temperature which reads on “temperature control apparatus”, and Hanson teaches the recellularized liver in a bioreactor (see Examples 2-4); it is noted the claim does not limit to the location of the temperature control apparatus.
Regarding claim 18, the as filed specification does not define a “cleanroom”, and therefore the room Hanson’s recellularized liver is in, which comprises sterilization filters (see Example 3) and the ability to make a product for use in transplantation (see paragraph [0120]), reads on the broadest reasonable interpretation of “cleanroom”.
Regarding claim 19, the as filed specification does not define a “factory”, and therefore the building Hanson’s recellularized liver is in, which comprises the needed materials and equipment, such as bioreactors, to make the product of a recellularized liver (see Examples 1-4), reads on the broadest reasonable interpretation of “factory”.
Regarding claims 4 and 14, in certain circumstances, claims may be rejected under 35 U.S.C. § 102 and § 103 as alternative grounds. Common scenarios in which §§102/103 rejections are appropriate include when the reference discloses all the limitations of a claim except a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention. In the instant case, Hanson does not specifically teach the expression of LYVE-1 and STAB-2 are greater in a parenchymal niche (meaning any parenchymal area) relative to the expression in a large vessel (meaning any large vessel) and does not expressly teach consumption of glucose at a rate of at least about 10 mg/hr for at least about 24 hours. However, as stated above, Hanson teaches that the recellularized liver comprises the liver cells, including sinusoidal endothelial cells expressing LYVE-1, localized to locations in the scaffold corresponding to those in vivo (see paragraph [0145]), while Dingle is evidence that the sinusoidal endothelial cells in the parenchyma, which is most of the liver mass and reads on “parenchymal niche” express LYVE-1, and Sancho-Bru is cited solely as evidence that STAB-2 is also expressed by liver sinusoidal endothelial cells. Therefore, for the reasons discussed above, it appears that Hanson’s recellularized liver is the same as the claimed product of a recellularized liver, and therefore would have the same properties including expression of LYVE-1 and STAB-2 at greater levels in a parenchymal niche relative to the expression in a large vessel. Hanson as set forth above teaches that the recellularized liver consumes glucose in media.
Once a product appearing to be substantially identical is found and an art rejection made, the burden shifts to the applicant to show an unobvious difference. In this case, if a prior-art reference teaches a recellularized liver that appears to be substantially identical to the claimed recellularized liver, applicants bear the burden of demonstrating by evidence that the elements in the product-by-process limitation impart structural properties to the recellularized liver that are different from those possessed by the prior-art reference’s recellularized liver. See M.P.E.P. § 2112. Hanson’s recellularized liver composition is thus substantially similar to the claimed composition and so the burden remains shifted to Applicant to overcome the 102 rejection by showing the prior art product lacks the claimed function/property, and then to overcome the 103 rejection by further showing that any different in the claimed function/property is non-obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Hanson as evidenced Sancho-Bru and Dingle as applied to claim 4 above, and further in view of Taylor et al (U.S.PGPUB 20130156744) and Dingle et al (2018, Angiogenesis, 21:581–597).
The teachings of Hanson as evidenced Sancho-Bru and Dingle are relied upon as set forth above.
Regarding claim 12, Hanson as evidenced Sancho-Bru and Dingle does not teach the endothelial cells are human umbilical vein endothelial cells (HUVECs).
Regarding claim 12 Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization (see paragraphs [0005] – [0012] and claims 1 &2).
Regarding claim 12, Dingle further teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization (see col. 1 on page 582).
It would have been obvious to combine Hanson with Taylor and Dingle to include HUVECs in Hanson’s recellularized liver. A person of ordinary skill in the art would have had a reasonable expectation of success in including HUVECs in Hanson’s recellularized liver because like Hanson, Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization. The skilled artisan would have been motivated to include HUVECs in Hanson’s recellularized liver because Dingle teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 4-6, 13, 14 and 16-19 remain rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-52 of U.S. Patent No. 10,441,609,
claims 1-26 of U.S. Patent No. 10,220,056,
claims 1-24 of U.S. Patent No. 11,278,643,
claims 1-24 of U.S. Patent No. 10,213,525, or alternatively
claims 10-16 of U.S. Patent No. 9,974,814,
when any are taken in view of Hanson et al (U.S.PGPUB 20170369849), as evidenced by Dingle et al (2018, Angiogenesis, 21:581–597) and Sancho-Bru et al (U.S.PGPUB 20120009672).
Patent ‘609 claims a product and methods of making a recellularized liver by perfusion of extracellular matrix of a decellularized liver that retains the morphology of said extracellular matrix prior to decellularization from one animal, with endothelial cells from another animal, wherein recellularized organ comprises a cannula and/or bioreactor.
Patent ‘056 claims a product and methods of making a recellularized organ, including liver or kidney, wherein the decellularized organ comprises comprising a non-vasculature decellularized extracellular matrix and vasculature decellularized extracellular matrix, that is recellularized organ comprises a cannula.
Patent ‘643 claims a methods of making a recellularized liver by perfusion of a decellularized isolated extracellular matrix of a liver with endothelial cells.
Patent ‘525 claims a methods of making a recellularized liver by perfusion of a decellularized isolated extracellular matrix of a liver with endothelial cells.
Patent ‘814 claims a methods of making a product by introducing cells into a decellularized extracellular matrix of an organ that comprises an intact exterior surface, wherein said extracellular matrix of said organ or portion thereof, or tissue or portion thereof, comprises a vascular tree, wherein the organ is a liver.
Regarding instant claims 4-6, 13, 14, and 16-19, none of the reference patents claim all of the features, such that the recellularized liver product comprises human endothelial cells and expresses LYVE-1 as claimed.
Regarding claims 4, 6, and 13, Hanson teaches a recellularized liver comprising a rat liver extracellular biomatrix scaffold (reads on first animal being a rodent) that is decellularized by perfusion through a cannula inserted into the portal vein of the liver, and recellularized with human cells (reads on second animal being a human), such that the cells recellularize the extracellular biomatrix scaffold with cells including endothelial cells (see Examples 2 & 4 and paragraphs [0172]). Regarding claim 13, Hanson teaches that the perfusion portal vein of the liver was also used to perfuse cells for recellularization (see Example 4), and therefore combined Hanson’s teaching that perfusion was done through a cannula inserted into the portal vein of the liver, this reads on the product further comprising a cannula. Regarding claims 4-5, Hanson teaches biomatrix is a three-dimensional decellularized scaffold that retains its native three-dimensional structure, including vasculature components (see paragraphs [0047], [0102], [0118] and [0172] and Figure 1); reads on including a vasculature and non-vasculature, and substantially intact exterior surface. Regarding claim 4, Hanson teaches that the recellularized liver consumes glucose in media (see paragraphs [0026] and [0164], Figures 9A-9C).
Regarding claims 4 and 14, Hanson teaches the recellularized liver comprised sinusoidal endothelial cells expressing LYVE-1 localized to locations in the scaffold corresponding to those in vivo (see paragraph [0145] and Figure 3). Regarding claim 4, Dingle is cited solely as evidence that LYVE-1 is expressed in the parenchymal areas of the liver by sinusoidal endothelial cells (see Figure 1, especially 1b, and col. 1 on pages 588 & 596); therefore, Dingle is evidence that the endothelial cells in the parenchyma, which is most of the liver mass and reads on “parenchymal niche” express LYVE-1. Similarly, regarding claim 14, Sancho-Bru is cited solely as evidence that STAB-2 is also expressed by liver sinusoidal endothelial cells (the same cell type as discussed in Hanson and Dingle) (see paragraph [0009]). Therefore, this reads on wherein the isolated at least partially recellularized liver comprises a greater expression level of LYVE- 1 or STAB-2 in a parenchymal niche of the isolated at least partially recellularized liver relative to an expression level of LYVE- 1 or STAB-2 in a large vessel of the isolated at least partially recellularized liver as Dingle shows more parenchymal tissue than any one large vessel with expression and Sancho-Bru teaches these same cells express STAB-2.
Regarding the limitation in claim 4 “wherein the isolated at least partially recellularized liver in media consumes glucose at a rate of at least about 10 mg/hr for at least about 24 hours”, Hanson teaches that the recellularized liver consumes glucose in media (see paragraphs [0026] and [0164], Figures 9A-9C). Furthermore, as it appears that the product of a recellularized liver as taught in the references is the same as the claimed product of a recellularized liver, the reference recellularized liver would have the same properties including the ability to consume glucose at a rate of at least about 10 mg/hr for at least about 24 hours absent any showing of inoperability to the contrary.
Regarding claim 16, Hanson teaches kit comprising the recellularized liver in a container with media, Hanson exemplifies using sterile filtered media, and teaches that the recellularized liver can be used for transplantation (see Example 3, and paragraphs [0005], [0016], [0120]-[0121] and [0172]); taken together, these teachings provide for a sterile container.
Regarding claim 17, Hanson teaches the perfusion connected to the recellularized liver comprises an attached input and output, growth media, and Hanson teaches holding the cells at a specific temperature which reads on “temperature control apparatus”, and Hanson teaches the recellularized liver in a bioreactor (see Examples 2-4); it is noted the claim does not limit to the location of the temperature control apparatus.
Regarding claim 18, the as filed specification does not define a “cleanroom”, and therefore the room Hanson’s recellularized liver is in, which comprises sterilization filters (see Example 3) and the ability to make a product for use in transplantation (see paragraph [0120]), reads on the broadest reasonable interpretation of “cleanroom”.
Regarding claim 19, the as filed specification does not define a “factory”, and therefore the building Hanson’s recellularized liver is in, which comprises the needed materials and equipment, such as bioreactors, to make the product of a recellularized liver (see Examples 1-4), reads on the broadest reasonable interpretation of “factory”.
It would have been obvious to combine any of the reference patents with Hanson to incorporate the features of Hanson’s recellularized liver product, as evidenced by Dingle and Sancho-Bru, into the methods and products of recellularized livers in the reference patents. A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the features of Hanson’s recellularized liver product, as evidenced by Dingle and Sancho-Bru, into the methods and products of recellularized livers in the reference patents because like the reference patents, Hanson teaches recellularization of decellularized livers. The skilled artisan would have been motivated to incorporate the features of Hanson’s recellularized liver product, as evidenced by Dingle and Sancho-Bru, into the methods and products of recellularized livers in the reference patents because Hanson establishes that each of these features are useful; "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See M.P.E.P. § 2144.06. Also, . “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claim 12 remains rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-52 of U.S. Patent No. 10,441,609,
claims 1-26 of U.S. Patent No. 10,220,056,
claims 1-24 of U.S. Patent No. 11,278,643,
claims 1-24 of U.S. Patent No. 10,213,525, or alternatively
claims 10-16 of U.S. Patent No. 9,974,814,
in view of Hanson and as evidenced by Dingle and Sancho-Bru as applied to claim 4 above, and in further view of Taylor et al (U.S.PGPUB 20130156744) and Dingle et al (2018, Angiogenesis, 21:581–597).
The teachings of the reference patents in view of Hanson as evidenced by Dingle and Sancho-Bru are relied upon as set forth above.
Regarding claim 12, the reference patents do not claim the endothelial cells are human umbilical vein endothelial cells (HUVECs).
Regarding claim 12, Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization (see paragraphs [0005] – [0012] and claims 1 &2).
Regarding claim 12, Dingle further teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization (see col. 1 on page 582).
It would have been obvious to combine the reference patents with Taylor and Dingle to include HUVECs in the patent’s recellularized liver. A person of ordinary skill in the art would have had a reasonable expectation of success in including HUVECs in Hanson’s recellularized liver because like the patents, Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization. The skilled artisan would have been motivated to include HUVECs in the patent’s recellularized liver because Dingle teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization.
Claims 4-6, 13, 14 and 16-19 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/394,243 in view of Hanson et al (U.S.PGPUB 20170369849), as evidenced by Dingle et al (2018, Angiogenesis, 21:581–597) and Sancho-Bru et al (U.S.PGPUB 20120009672).
Application ‘243 claims methods of making a recellularized liver by perfusion of a decellularized isolated extracellular matrix of a liver with endothelial cells.
Application ‘814 claims a product of a decellularized isolated extracellular matrix of a liver cells.
Regarding instant claims 4-6, 13, 14, and 16-19, the two reference applications do not claim all of the features, such that the recellularized liver product comprises endothelial cells and expresses LYVE-1 as claimed.
Regarding claims 4, 6, and 13, Hanson teaches a recellularized liver comprising a rat liver extracellular biomatrix scaffold (reads on first animal being a rodent) that is decellularized by perfusion through a cannula inserted into the portal vein of the liver, and recellularized with human cells (reads on second animal being a human), such that the cells recellularize the extracellular biomatrix scaffold with cells including endothelial cells (see Examples 2 & 4 and paragraphs [0172]). Regarding claim 13, Hanson teaches that the perfusion portal vein of the liver was also used to perfuse cells for recellularization (see Example 4), and therefore combined Hanson’s teaching that perfusion was done through a cannula inserted into the portal vein of the liver, this reads on the product further comprising a cannula. Regarding claims 4-5, Hanson teaches biomatrix is a three-dimensional decellularized scaffold that retains its native three-dimensional structure, including vasculature components (see paragraphs [0047], [0102], [0118] and [0172] and Figure 1); reads on including a vasculature and non-vasculature, and substantially intact exterior surface. Regarding claim 4, Hanson teaches that the recellularized liver consumes glucose in media (see paragraphs [0026] and [0164], Figures 9A-9C).
Regarding claims 4 and 14, Hanson teaches the recellularized liver comprised sinusoidal endothelial cells expressing LYVE-1 localized to locations in the scaffold corresponding to those in vivo (see paragraph [0145] and Figure 3). Regarding claim 4, Dingle is cited solely as evidence that LYVE-1 is expressed in the parenchymal areas of the liver by sinusoidal endothelial cells (see Figure 1, especially 1b, and col. 1 on pages 588 & 596); therefore, Dingle is evidence that the endothelial cells in the parenchyma, which is most of the liver mass and reads on “parenchymal niche” express LYVE-1. Similarly, regarding claim 14, Sancho-Bru is cited solely as evidence that STAB-2 is also expressed by liver sinusoidal endothelial cells (the same cell type as discussed in Hanson and Dingle) (see paragraph [0009]). Therefore, this reads on wherein the isolated at least partially recellularized liver comprises a greater expression level of LYVE- 1 or STAB-2 in a parenchymal niche of the isolated at least partially recellularized liver relative to an expression level of LYVE- 1 or STAB-2 in a large vessel of the isolated at least partially recellularized liver as Dingle shows more parenchymal tissue than any one large vessel with expression and Sancho-Bru teaches these same cells express STAB-2.
Regarding the limitation in claim 4 “wherein the isolated at least partially recellularized liver in media consumes glucose at a rate of at least about 10 mg/hr for at least about 24 hours”, Hanson teaches that the recellularized liver consumes glucose in media (see paragraphs [0026] and [0164], Figures 9A-9C). Furthermore, as it appears that the product of a recellularized liver as taught in the references is the same as the claimed product of a recellularized liver, the reference recellularized liver would have the same properties including the ability to consume glucose at a rate of at least about 10 mg/hr for at least about 24 hours. Therefore, the reference product reads on the claim absent any persuasive showing to the contrary.
Regarding claim 16, Hanson teaches kit comprising the recellularized liver in a container with media, Hanson exemplifies using sterile filtered media, and teaches that the recellularized liver can be used for transplantation (see Example 3, and paragraphs [0005], [0016], [0120]-[0121] and [0172]); taken together, these teachings provide for a sterile container.
Regarding claim 17, Hanson teaches the perfusion connected to the recellularized liver comprises an attached input and output, growth media, and Hanson teaches holding the cells at a specific temperature which reads on “temperature control apparatus”, and Hanson teaches the recellularized liver in a bioreactor (see Examples 2-4); it is noted the claim does not limit to the location of the temperature control apparatus.
Regarding claim 18, the as filed specification does not define a “cleanroom”, and therefore the room Hanson’s recellularized liver is in, which comprises sterilization filters (see Example 3) and the ability to make a product for use in transplantation (see paragraph [0120]), reads on the broadest reasonable interpretation of “cleanroom”.
Regarding claim 19, the as filed specification does not define a “factory”, and therefore the building Hanson’s recellularized liver is in, which comprises the needed materials and equipment, such as bioreactors, to make the product of a recellularized liver (see Examples 1-4), reads on the broadest reasonable interpretation of “factory”.
It would have been obvious to combine any of the applications with Hanson to incorporate the features of Hanson’s recellularized liver product, as evidenced by the inherency references, into the methods and products of recellularized livers in the reference applications. A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the features of Hanson’s recellularized liver product, as evidenced by the inherency references, into the methods and products of recellularized livers in the reference applications because like the reference patents, Hanson teaches recellularization of decellularized livers. The skilled artisan would have been motivated to incorporate the features of Hanson’s recellularized liver product, as evidenced by the inherency references, into the methods and products of recellularized livers in the reference applications because Hanson establishes that each of these features are useful.
Regarding claims 4 and 16, in certain circumstances, claims may be rejected under 35 U.S.C. § 102 and § 103 as alternative grounds. Common scenarios in which §§102/103 rejections are appropriate include when the reference discloses all the limitations of a claim except a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention. In the instant case, Hanson does not specifically teach the expression of LYVE-1 and STAB-2 are greater in a parenchymal niche (meaning any parenchymal area) relative to the expression in a large vessel (meaning any large vessel) and does not expressly teach consumption of glucose at a rate of at least about 10 mg/hr for at least about 24 hours. However, as stated above, Hanson teaches that the recellularized liver comprises the liver cells, including sinusoidal endothelial cells expressing LYVE-1, localized to locations in the scaffold corresponding to those in vivo (see paragraph [0145]), while Dingle is evidence that the sinusoidal endothelial cells in the parenchyma, which is most of the liver mass and reads on “parenchymal niche” express LYVE-1, and Sancho-Bru is cited solely as evidence that STAB-2 is also expressed by liver sinusoidal endothelial cells. Therefore, for the reasons discussed above, it appears that Hanson’s recellularized liver is the same as the claimed product of a recellularized liver, and therefore would have the same properties including expression of LYVE-1 and STAB-2 at greater levels in a parenchymal niche relative to the expression in a large vessel. Hanson as set forth above teaches that the recellularized liver consumes glucose in media. Regarding claim 16, as discussed above, it appears that Hanson’s container in Hanson’s kit is sterile since Hanson’s kit comprises the recellularized liver in a container with media, Hanson exemplifies using sterile filtered media, and teaches that the recellularized liver can be used for transplantation. Taken together, these teachings provide for a sterile container.
Once a product appearing to be substantially identical is found and an art rejection made, the burden shifts to the applicant to show an unobvious difference. In this case, if a prior-art reference teaches a recellularized liver that appears to be substantially identical to the claimed recellularized liver, applicants bear the burden of demonstrating by evidence that the elements in the product-by-process limitation impart structural properties to the recellularized liver that are different from those possessed by the prior-art reference’s recellularized liver. See M.P.E.P. § 2112. Hanson’s recellularized liver composition is thus substantially similar to the claimed composition and so the burden remains shifted to Applicant to overcome the 102 rejection by showing the prior art product lacks the claimed function/property, and then to overcome the 103 rejection by further showing that any different in the claimed function/property is non-obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
This is a provisional nonstatutory double patenting rejection.
Claim 12 remains provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/394,243 in view of Hanson as evidenced by Dingle and Sancho-Bru et al as applied to claim 4 above, and in further view of Taylor et al (U.S.PGPUB 20130156744) and Dingle et al (2018, Angiogenesis, 21:581–597).
The teachings of the reference applications in view of Hanson as evidenced by Dingle and Sancho-Bru are relied upon as set forth above.
Regarding claim 12, the reference applications do not claim the endothelial cells are human umbilical vein endothelial cells (HUVECs).
Regarding claim 12, like the patents, Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization (see paragraphs [0005] – [0012] and claims 1 &2).
Regarding claim 12, Dingle teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization (see col. 1 on page 582).
It would have been obvious to combine the applications with Taylor and Dingle to include HUVECs in the application’s recellularized liver. A person of ordinary skill in the art would have had a reasonable expectation of success in including HUVECs in Hanson’s recellularized liver because like the applications, Taylor teaches methods of recellularizing organs including livers, and Taylor teaches that HUVECs are a cell type that is useful for said recellularization. The skilled artisan would have been motivated to include HUVECs in the application’s recellularized liver because Dingle teaches for liver tissue engineering, co-implantation of HUVECs incorporated with other liver cells has been shown to improved vascularization.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments on pages 5-15 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On page 8-9 of the reply, Applicant alleges that Hanson is deficient by not teaching every element of independent claim 4. This is not persuasive because Applicant has not yet shown by any preponderance of evidence that Hanson as evidenced by Dingle and Sancho-Bru is not capable of meeting the functional properties of claimed isolated and partially recellularized liver. In other words, Hanson teaches a substantially identical composition, and the burden remains with shifted back to Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product; see M.P.E.P. § 2112(V) and 2112.01(I). Also see M.P.E.P. § 716.01(c) in that statements of inoperability of the prior art must be factually supported by an appropriate affidavit or declaration, and M.P.E.P. § 716.07 in that the prior art is presumed operable absent a preponderance of evidence to the contrary.
Applicants rely on arguments traversing the above rejection of claim 4 alternatively under 35 U.S.C. § 102 and 103 to traverse the rejection of claim 12 in view of Taylor on pages 9-11 of the reply. Therefore, the response set forth above to arguments also applies to this rejection. Applicant’s arguments rely entirely on the features of claim 4, and do not address the specific rationale and motivation to a person of ordinary skill in the art to add the HUVECs of Taylor to the liver of Hanson as evidenced by Dingle and Sancho-Bru.
Applicant’s arguments regarding the non-statutory double patenting rejections of record on pages 11-13 of the reply are acknowledged, over:
US Patent Nos: 10,441,609; 10,220,056; 11,278,643; 10,213,525; and 9,974,814,
US Application No: 17/394,243,
The arguments are not found persuasive because they rely on the above arguments over Hanson with respect to the alternative 35 U.S.C. § 102 and 103 rejections of record, continuing to allege without any factual basis that Hanson cannot meet glucose consumption functional properties of claim 1. This is not persuasive for the reasons given above, briefly restated that Applicant has not yet shown the alleged inoperability of Hanson by any preponderance of factual evidence.
Applicant’s further arguments on pages 13-14 of the reply regarding the nonstatutory double patenting rejections of record are not persuasive error, as they amount to a general allegation of patentably distinct subject matter without clearly pointing out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made, and the arguments do not show how the amendments avoid such issued patents and copending applications in view of Hanson and as evidenced by Dingle and Sancho-Bru.
Conclusion
No claims are allowed. No claims are free of the art.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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