DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Applicant’s submission filed 29 December 2025 has been entered. Claims 1, 6-10, 22, 28, 63-71, and 73-91 are pending. Claims 1, 8-10, 28, 63-64, 69-70 have been amended, while claims 5, 62, and 72 have been cancelled without prejudice or disclaimer and claims 73-91 have been newly added. Therefore, examination on the merits continues for claims 1, 6-10, 22, 28, 63-71, and 73-91 as being drawn to the elected invention. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to the Specification
Applicant has failed to address the objection to the Specification of record in the Office action filed 28 July 2025.
Therefore, the objection is maintained.
RE: Objection to claims 28, 62-64, and 72
The cancellation of claims 62 and 72 renders the objections moot for those claims. For the remaining claims, Applicant’s amendments to each of claims 28 and 63-64 obviate the objections of record.
Therefore, the objections are withdrawn.
RE: Rejection of claims 1, 5-10, 22, 28, and 62-72 under 35 USC 112(b)
The cancellation of claims 5, 62, and 72 renders the rejections moot for those claims. For the remaining claims, Applicant’s amendment to independent claim 28 obviate the rejection of record. However, Applicant’s arguments regarding independent claim 1 in the Remarks filed 29 December 2025 are not persuasive, as the ordinary artisan would still not be able to readily determine the scope of the “strained” substrate even in light of the Specification. In addition, Applicant has failed to address the rejection of record regarding instant claim 63.
Therefore, the rejection is withdrawn for claim 28 and maintained for claims 1, 6-10, 22, and 63-71.
RE: Rejection of claim 6 under 35 USC 112(d)
Applicant’s amendments to parent claim 1 obviate the rejection of record regarding instant claim 6.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 6, 62-64, 66, and 68-72 under 35 USC 102(a)(1) over Yuan et al
The cancellation of claims 62 and 72 renders the rejection moot for those claims. For the remaining claims, Applicant’s amendments to independent claim 1 requiring the strained substrate to (i) have a thickness of about 0.1 μm to 10 μm, and (ii) comprise discrete layers of at least one of human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC) obviate the rejection of record.
Therefore, the rejection is withdrawn.
However, Applicant’s arguments are addressed in so far as they are applicable to the new
rejection of record:
Applicant has traversed the rejection, asserting in Pages 13-14 of the Remarks filed 29 December 2025 that the vessel wall modulus and dimensions, as well as the patterning of the extracellular matrix proteins within the vessel walls, allows for “enhanced results”. In response, the Examiner respectfully reminds Applicant that when submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP § 716.02(b). In the instant case, Applicant has failed to indicate how the alleged unexpected results differ from the closest prior art.
RE: Rejection of claims 1, 5-10, 28, 62-64, 66, and 68-72 under 35 USC 103 over Yuan et al in view of Imperial College London
The cancellation of claims 5, 62, and 72 renders the rejection moot for those claims. For the remaining claims, Applicant’s amendments to independent claim 1 requiring the strained substrate to (i) have a thickness of about 0.1 μm to 10 μm, and (ii) comprise discrete layers of at least one of human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC) obviate the rejection of record. In addition, Applicant’s amendments to independent claim 28 requiring the method to comprise the provision of one or more strained film layers over a sacrificial layer obviate the rejection of record.
Therefore, the rejection is withdrawn.
However, Applicant’s arguments are addressed in so far as they are applicable to the new
rejection of record:
Applicant has traversed the rejection, asserting in Page 11 of the Remarks filed 29 December 2025 that the utilization of a sacrificial layer for the self-rolling of the cell sheets results in precisely layered co-cultures having a tubular geometry. In response, the Examiner respectfully submits that Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. However, if Applicant is instead pointing out unexpected results from performing the instant claims, the Examiner respectfully reminds Applicant that when submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP § 716.02(b). In the instant case, Applicant has failed to indicate how the alleged unexpected results differ from the closest prior art.
RE: Rejection of claims 1, 5-10, 22, 28, 62-64, 66, and 68-72 under 35 USC 103 over Yuan et al in view of Imperial College London and Miklas et al
The cancellation of claims 5, 62, and 72 renders the rejection moot for those claims. For the remaining claims, Applicant’s amendments to independent claim 1 requiring the strained substrate to (i) have a thickness of about 0.1 μm to 10 μm, and (ii) comprise discrete layers of at least one of human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC) obviate the rejection of record. In addition, Applicant’s amendments to independent claim 28 requiring the method to comprise the provision of one or more strained film layers over a sacrificial layer obviate the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 6, 62-66, and 68-72 under 35 USC 103 over Yuan et al in view of Liu et al
The cancellation of claims 62 and 72 renders the rejection moot for those claims. For the remaining claims, Applicant’s amendments to independent claim 1 requiring the strained substrate to (i) have a thickness of about 0.1 μm to 10 μm, and (ii) comprise discrete layers of at least one of human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC) obviate the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 6, 62-64, and 66-72 under 35 USC 103 over Yuan et al in view of Miklas et al
The cancellation of claims 62 and 72 renders the rejection moot for those claims. For the remaining claims, Applicant’s amendments to independent claim 1 requiring the strained substrate to (i) have a thickness of about 0.1 μm to 10 μm, and (ii) comprise discrete layers of at least one of human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC) obviate the rejection of record.
Therefore, the rejection is withdrawn.
New/Maintained Grounds of Rejection
Specification
The instant Specification is still objected for referencing colors within the figures, when colored drawings have not submitted in the application. More specifically, the Specification references colors at least within Pages 16-19 in reference to Figures 1, 3, 7, 10, 12, and 17. Applicant is requested to review the Specification to identify any additional references to colors within the drawings and delete as appropriate since black and white drawings are submitted. The Specification must be amended to delete reference to specific colors within the text of the Specification.
Appropriate correction is required.
Claim Objections
Instant claim 28 is objected to because of the following informalities:
Regarding claim 28: Each claim should begin with a capital letter and end with a period. Periods
may not be used elsewhere in the claims except for abbreviations. See MPEP § 608.01(m). Therefore, the comma at the end of the claim must be replaced with a period.
Appropriate correction is required.
Claim Interpretation
Instant claim 69 defines the composition comprising a biomimetic in vitro model of a pulmonary vessel as being comprised of a strained substrate that has human smooth muscle cells and human endothelial cells sequentially layered onto the substrate. This is a product-by-process limitation. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the sequential layering of the smooth muscle cells and endothelial cells onto the substrate imparts any particular structure or significance to the composition other than the cells being in discrete, overlaying monolayers that are situated around the inner circumference of the final vessel model. Thus, the claim will be interpreted as if a composition comprising a biomimetic in vitro model of a pulmonary vessel that comprises discrete, overlaying monolayers that are situated around the inner circumference of the final vessel model fulfills the sequential layering that is required by the instant claim.
Instant claim 71 defines the composition comprising a biomimetic in vitro model of a pulmonary vessel as being self-folded. This is a product-by-process limitation. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the self-folding of the composition imparts any particular structure or significance to the composition other than it being in a final tubular orientation. Thus, the claim will be interpreted as if a composition comprising a biomimetic in vitro model of a pulmonary vessel that has an overall tubular geometry fulfills the self-folded feature that is required by the instant claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-10, 22, 63-71, 73-78, and 88-91 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 22, 88: Each of independent claims 1, 22, and 88 either directly recite of fully incorporate the limitation requiring the pulmonary vessel model to comprise a “strained” substrate. The scope of each claim is indefinite, as the recitation of a “strained” substrate implies that the substrate is currently in a strained state. However, when looking to the instant Specification and the teachings of the prior art, the ordinary artisan would understand that, in order to recapitulate the tubular model, the substrate must be pre-strained (or pre-stretched) and then released to self-fold into a tubular structure. See, for example, Figure 1 and Page 43 of the instant Specification, wherein the PDMS membranes are exposed to stretch first before self-folding into a tubular structure, or the stress-induced rolling membrane technique detailed in Yuan et al (see below). Therefore, the ordinary artisan cannot readily determine the metes and bounds of the instant claims.
Claims 5-10, 63-71, 73-78, and 89-91 directly depend upon claims 1 and 88, and are thus rendered indefinite as well.
Appropriate correction is required.
Regarding claim 63: The instant claim recites the limitation, “wherein the smooth muscle cells are aligned in parallel.” The scope of the claim is further indefinite, as it is unclear what the smooth muscle cells are aligned in parallel to. Therefore, the ordinary artisan cannot readily determine the metes and bounds of the claim.
Appropriate correction is required.
Regarding claim 70: The instant claim is dependent upon cancelled claim 62. Therefore, the ordinary artisan cannot readily determine the metes and bounds of the claim. For the sake of compact prosecution, the instant claim will be examined as if it is dependent from parent claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1, 6-10, 63-64, 66, 68-71, 74-75, and 77-78 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Imperial College London (YouTube, 2016, of record).
Yuan et is considered prior art under 35 USC 102(a)(1). It is of note that Yuan et al is now provided with the accompanying supplemental information. Imperial College of London is considered prior art under 35 USC 102(a)(1).
Regarding claims 1, 6-7, 10, 71, and 74: Yuan et al disclose biomimetic tubular models of vessels, wherein a stress-induced rolling membrane (SIRM) technique is utilized (Page 890, Column 1; Page 893, Column 2).
As such, Yuan et al disclose that the SIRM technique involves the delivering and patterning of human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts onto a two-dimensional polydimethylsiloxane (PDMS) SIRM using microfluidic channels, and then releasing the SIRM to roll up – or self-fold – into a three-dimensional tube (Page 890, Columns 1-2; Page 891, Columns 1-2; Pages 893-894, Fabrication; Page 895, Cell Culture and Staining; Figures 1-2, 5).
Yuan et al further disclose that the PDMS membrane has a thickness of about 10 microns (Figure S2).
Yuan et al further disclose that the biomimetic tubular structures can be utilized to model any tubular tissue via the customization of the seeded cells, including the trachea, blood vessels, lymph vessels, and intestines (Page 890, Columns 1-2).
Yuan et al do not disclose that the human smooth muscle cells and endothelial cells are human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC), as required by instant claim 1.
Imperial College London, however, disclose a three-dimensional model of a lung blood vessel on a microchip, wherein the lung blood vessel is comprised of human patient-derived pulmonary smooth muscle cells and endothelial cells (Page 2; Page 4, 1:06-1:26, 1:27-1:41, 1:52-2:08).
Therefore, it would have been prima facie obvious to have modified the biomimetic tubular vessel of Yuan et al to generate a biomimetic pulmonary vessel using human patient-derived pulmonary artery smooth muscle cells and endothelial cells, as detailed in the video produced by Imperial College London. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to generate a biomimetic pulmonary vessel model, as it allows for the ability to investigate changes that happen in the diseased lung blood vessels and test individual patient’s responses to drugs in a highly controlled environment (Imperial College London, Page 5, 2:09-2:23). Furthermore, the ordinary artisan would have had a reasonable expectation of success based on the disclosure of Imperial College London combined with the protocols outlined in Yuan et al – especially as both are concerned with the generation of vessel models. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular in vitro model of a pulmonary vessel, wherein discrete monolayers (claim 7) of human-derived pulmonary artery smooth muscle cells and endothelial cells (claim 6) and fibroblasts are seeded onto a pre-strained two-dimensional polydimethylsiloxane (PDMS) membrane (claim 10), and then allowed to self-fold (claim 71) into a three-dimensional tubular structure. As the pre-strained PDMS membrane has a thickness of about 10 microns (claim 74), this therefore render obvious the composition of instant claim 1.
Regarding claim 8: Following the discussion of claim 1, Yuan et al further disclose that the PDMS is an elastomeric membrane (Page 890, Column 2). This therefore reads on the composition of the instant claim.
Regarding claims 9, 63-64, 68, and 77: Following the discussion of claim 1, Yuan et al further disclose that the pre-strained PDMS membrane is patterned (claims 9, 68) with microgrooves to allow for the smooth muscle cells to be aligned either parallel (claim 63) or perpendicular (claim 64) to the long axis of the self-folded tubular structure (claim 77)(Page 891, Column 1; Page 893, Column 1; Figures 1, 4). This therefore reads on the composition of the instant claims.
Regarding claim 66: Following the discussion of claim 1, Yuan et al further disclose that the vessel model size can be tuned via the initial thickness and stress applied to the PDMS membrane (Page 891, Column 1-2; Page 893, Column 2; Figure 2). This therefore reads on the composition of the instant claim.
Regarding claims 69-70: Instant claim 69 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
Following the discussion of claim 1, Yuan et al further disclose that the human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts are sequentially seeded – or layered – onto the pre-strained PDMS membrane, which is patterned such that the smooth muscle cells are aligned in parallel along the long axis of unidirectional (claim 70) microgrooves. This therefore reads on the composition of instant claim 69.
Regarding claim 75: Following the discussion of claim 1, Yuan et al further disclose that the inner diameter – or lumen – of the vessel is from about 100 microns to 2 mm (Page 891, Column 2). As this overlaps with the claimed range of 25 microns to 200 microns, this therefore renders obvious the composition of the instant claim. See MPEP § 2144.05.
Regarding claim 78: Following the discussion of claim 1, Yuan et al further discloses that fibronectin is added to promote cell adhesion of the patterned smooth muscle cells to the pre-stretched PDMS membrane (Page 894, Column 2; Figure 4). This therefore reads on the composition of the instant claim.
Claims 1, 6-10, 22, 63-64, 66-71, 74-75, and 77-78 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Imperial College London (YouTube, 2016, of record) and further in view of Miklas et al (US 2016/0282338 A1, of record).
The discussion of Yuan et al as modified by Imperial College London regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Imperial College London render obvious claims 1, 6-10, 63-64, 66, 68-71, 74-75, and 77-78. Miklas et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 22: As aforementioned in the discussion of claim 1 above, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular models of pulmonary vessels, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns, and then allowed to self-fold into a three-dimensional tubular structure.
Imperial College London further disclose the generation of a biomimetic pulmonary artery model that allows for the testing of multiple drugs – including pulmonary arterial hypertension therapeutics (Page 4, 0:08-0:18, 1:52-2:08; Page 5).
The combination of Yuan et al and Imperial College London fail to teach the induction of the biomimetic tubular vessel to exhibit pulmonary arterial hypertension (PAH), nor administering a candidate compound to the biomimetic tubular vessel and determining its effect on the PAH, as required by instant claim 22.
Miklas et al, however, disclose an engineered three-dimensional tissue comprised of layered smooth muscle cells and endothelial cells that recapitulates at least the overall tubular geometry, including turns and folds, and cellular alignment of an in vivo vessel (Paragraphs [0504]-[0505], [0511], [0514], [0681]). Miklas et al further disclose that the engineered vessel can be used in various applications, including, but not limited to, (a) the testing of the efficacy and safety of experimental pharmacologic agents, (b) the defining of pharmacokinetics and/or pharmacodynamics of pharmacologic agents, (c) characterizing the properties and therapeutic effects of pharmacologic agents on a subject, (d) screening of new pharmacologic agents, (e) providing implantable engineered tissues for use in regenerative medicine for treating damaged and/or diseased tissues, and (f) personalized medicine (Paragraph [0015]).
With that, Miklas et al disclose a method for evaluating the safety and efficacy of a test agent on a tissue, comprising: (a) contacting the three-dimensional tissue construct with a test agent; (b) measuring the effect on one or more physiological parameters indicative of safety and/or efficacy; comparing (b) to the same physiological parameter measured from a control three-dimensional tissue construct not exposed to the test agent, wherein a statistically significant change in the physiological parameter in (b) as compared to (c) indicates that the test agent lacks safety and/or efficacy (Paragraph [0054]).
Miklas et al further disclose that, in some embodiments, the three-dimensional tissue constructs utilized within the safety and efficacy testing can be altered using standard recombinant techniques to induce a disease state (Paragraph [0553]). Such diseases include atherosclerosis or hypertension (Paragraph [0569]).
Therefore, it would have been prima facie obvious to have utilized the biomimetic tubular vessel of Yuan et al and Imperial College London within the test agent screening method of Miklas et al to induce the biomimetic tubular vessel to exhibit pulmonary artery hypertension (PAH). One of ordinary skill before the effective filing date would have been motivated to create an in vitro model of the PAH disease state to subsequently study the changes that happen in the affected lung blood vessels and test individual patient’s responses to drugs in a highly controlled environment, and would have had a reasonable expectation of success based on the combined disclosures of Imperial College London and Miklas et al. See MPEP § 2143(I)(A) and 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London and Miklas et al render obvious a method of screening a test agent, wherein a biomimetic tubular vessel is induced to exhibit a pulmonary arterial hypertensive disease state, administered the test agent, and compared to a control biomimetic tubular vessel construct. This therefore renders obvious the method of the instant claim.
Regarding claim 67: As aforementioned in the discussion of claim 1 above, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular models of pulmonary vessels, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns, and then allowed to self-fold into a three-dimensional tubular structure.
Yuan et al further discloses that fibronectin is added to promote cell adhesion of the patterned smooth muscle cells to the pre-stretched PDMS membrane (Page 894, Column 2; Figure 4).
The combination of Yuan et al and Imperial College London fail to teach that the PDMS membrane further comprises one or more layers of laminin and fibronectin, as required by instant claim 67.
Miklas et al, however, disclose an engineered three-dimensional tissue comprised of sequentially layered smooth muscle cells and endothelial cells that recapitulates at least the overall tubular geometry, including turns and folds, and cellular alignment of an in vivo vessel (Paragraphs [0504]-[0505], [0511], [0514], [0681]).
Miklas et al further disclose that the engineered three-dimensional tissue can further comprise fibronectin and laminin (Paragraphs [0183], [0243], [0310], [0370], [0434]).
Therefore, it would have been prima facie obvious to modify the biomimetic tubular vessel of Yuan et al and Imperial College London such that the PDMS membrane further comprises layers of laminin and fibronectin, as detailed in Miklas et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to include these natural proteins, as they are known for their bioactive properties, specific cell recognition, cellular invasion, and the ability to supply differentiation/proliferation signals (Miklas et al: Paragraphs [0316], [0374], [0376]), and would have had a reasonable expectation of success based on the combined disclosures of Yuan et al and Miklas et al since both are concerned with the generation of vessel models. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London and Miklas et al render obvious a biomimetic tubular vessel, wherein the PDMS membrane further comprises layers of fibronectin and laminin. This therefore renders obvious the composition of the instant claim.
Claims 1, 6-10, 22, 63-64, 66-71, 74-78, and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Imperial College London (YouTube, 2016, of record) and Miklas et al (US 2016/0282338 A1, of record), and further in view of Sicard et al (J Mech Behav Biomed Mater, 2017).
The discussion of Yuan et al as modified by Imperial College London regarding claim 1 can be
observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Imperial College London render obvious claims 1, 6-10, 63-64, 66, 68-71, 74-75, and 77-78. Yuan et al as modified by Imperial College London and Miklas et al render obvious claims 1, 6-10, 22, 63-64, 66-71, 74-75, and 77-78. Sicard et al is considered prior art under 35 USC 102(a)(1), with an electronic publication date of 31 May 2017.
Regarding claims 76 and 88-90: As aforementioned in the discussion of claim 1 above, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular models of pulmonary vessels, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns, and then allowed to self-fold into a three-dimensional tubular structure.
Yuan et al further discloses that fibronectin is added to promote cell adhesion of the patterned smooth muscle cells to the pre-stretched PDMS membrane (Page 894, Column 2; Figure 4).
Yuan et al further disclose that the inner diameter – or lumen – of the vessel is from about 100 microns to 2 mm (Page 891, Column 2).
The combination of Yuan et al and Imperial College London fail to teach that the vessel wall modulus is about 0.1 to 15 kPa, as required by instant claims 76 and 88.
Miklas et al, however, disclose an engineered three-dimensional tissue comprised of layered smooth muscle cells and endothelial cells that recapitulates at least the overall tubular geometry, including turns and folds, and cellular alignment of an in vivo vessel (Paragraphs [0504]-[0505], [0511], [0514], [0681]).
Miklas et al further disclose that the engineered three-dimensional tissue has an elastic modulus that matches the tissue in which it is replacing and/or mimicking (Paragraph [0773]).
With that, Sicard et al disclose that the elastic modulus of human pulmonary arterial walls is about 5 kPa, with fluctuations in the measurement depending on the tissue thickness (Pages 122-123; Figures 3C-D).
Therefore, it would have been prima facie obvious to have modified the biomimetic tubular vessel of Yuan et al and Imperial College London to generate a biomimetic pulmonary vessel having an elastic modulus that matches the natural elastic modulus of human pulmonary arteries, as detailed in Miklas et al and Sicard et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to generate a biomimetic pulmonary vessel model having similar mechanical properties as the native tissue, as it simulates a native physiological environment for both in vitro and in vivo applications (Miklas et al: Paragraph [0773]). Furthermore, the ordinary artisan would have had a reasonable expectation of success since the biomimetic vessel of Yuan et al is highly tunable and it would not have been outside the skillset of the ordinary artisan to modulate the elastic modulus of the PDMS membranes. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London, Miklas et al, and Sicard et al render obvious a biomimetic tubular model of a pulmonary vessel, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns (claim 89) and comprising patterned fibronectin (claim 90), and then allowed to self-fold into a three-dimensional tubular structure having a vessel wall modulus of about 5 kPa (claim 76) and lumen diameter of about 100 microns to 2 mm (claim 91). As the lumen diameter range overlaps with the claimed range of 25 microns to 200 microns, this therefore renders obvious the composition of instant claim 88. See MPEP § 2144.05.
Claims 1, 6-10, 63-66, 68-71, 74-75, and 77-78 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Imperial College London (YouTube, 2016, of record), and further in view of Liu et al (Acta Biomaterialia, 2014, of record).
The discussion of Yuan et al as modified by Imperial College London regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Imperial College London render obvious claims 1, 6-10, 63-64, 66, 68-71, 74-75, and 77-78. Liu et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 65: As aforementioned in the discussion of claim 1 above, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular models of pulmonary vessels, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns, and then allowed to self-fold into a three-dimensional tubular structure.
Yuan et al further disclose that PDMS membrane is topographically patterned with microgrooves such that the smooth muscle cells can be aligned either parallel or perpendicular to the long axis of the self-folded vessel model (Page 891, Column 1; Page 893, Column 1; Figures 1, 4).
The combination of Yuan et al and Imperial College London fail to teach that the smooth muscle cells are aligned in an anatomically accurate helically striped pattern, as required by instant claim 65.
Liu et al, however, disclose the fabrication of engineered blood vessels, wherein smooth muscle cells and endothelial cells are seeded onto micropatterned fibrous mats (Abstract; Page 115, Column 2; Page 117, 2.6 and 2.7). Liu et al further disclose that the smooth muscle cells arranged into a helical pattern within the vessel (Page 122, Column 2; Page 124, 5).
Therefore, it would have been prima facie obvious to have modified the biomimetic tubular vessel of Yuan et al and Imperial College London such that the PDMS membrane is patterned in a way that allows for the helical arrangement of the smooth muscle cells, as detailed in Liu et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to produce an anatomically accurate vessel that recapitulates the smooth muscle cell patterning, and would have had a reasonable expectation of success based on the combined disclosures of Yuan et al and Liu et al. Furthermore, since the disclosures of both Yuan et al and Liu et al are concerned with the generation of topographically-patterned biomimetic vessels, there will be minimal adaptation required between the two methods. See MPEP § 2143(I)(A) and 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London and Liu et al render obvious a biomimetic tubular vessel, wherein the smooth muscle cells are arranged in an anatomically correct helically striped pattern. This therefore renders obvious the composition of the instant claim.
Claims 1, 6-10, 63-64, 66, 68-71, 73-75, and 77-78 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Imperial College London (YouTube, 2016, of record), and further in view of Hujaya et al (Pharm Res, 2015).
The discussion of Yuan et al as modified by Imperial College London regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Imperial College London render obvious claims 1, 6-10, 63-64, 66, 68-71, 74-75, and 77-78. Hujaya et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 73: As aforementioned in the discussion of claim 1 above, Yuan et al as modified by Imperial College London render obvious a biomimetic tubular models of pulmonary vessels, wherein discrete layers of human pulmonary endothelial cells, human pulmonary artery smooth muscle cells, and fibroblasts are seeded onto a pre-strained two-dimensional PDMS membrane having a thickness of about 10 microns, and then allowed to self-fold into a three-dimensional tubular structure.
Yuan et al further disclose that the PDMS membrane can instead be any elastic polymeric membrane (Page 890, Column 2).
The combination of Yuan et al and Imperial College London fail to teach that the pre-strained membrane comprises boronic acid-functional poly(amido) amines, as required by instant claim 73.
Hujaya et al, however, disclose the formation of thin films from poly(vinyl alcohol) (PVA) and phenylboronic acid-functional poly(amido amine)s (BA-PAA), which maintain their structural flexibility (Abstract; Pages 3067-3071, 3074; Figure 2). Hujaya et al further disclose that the PVA-based film was structurally stable under physiological conditions, and allows for the culturing of cells upon the film (Pages 3074, 3079-3084).
Therefore, it would have been prima facie obvious to have modified the biomimetic tubular vessel of Yuan et al and Imperial College London such that the membranes are fabricated from a PVA and BA-PAA co-polymer, as detailed in Hujaya et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize a PVA-based copolymer that is structurally stable under physiological conditions and is biocompatible, and would have had a reasonable expectation of success based on the combined disclosures of Yuan et al and Hujaya et al. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Imperial College London and Hujaya et al render obvious a biomimetic tubular vessel, wherein the pre-strained membrane comprises a PVA and BA-PAA co-polymer. This therefore renders obvious the composition of the instant claim.
Claims 28, 80-83, and 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Livermore-Clifford et al (US 2016/0032239 A1).
Yuan et is considered prior art under 35 USC 102(a)(1). It is of note that Yuan et al is now
provided with the accompanying supplemental information. Livermore-Clifford et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 28, 80, and 87: Yuan et al disclose a method of forming biomimetic tubular models of vessels, wherein a stress-induced rolling membrane (SIRM) technique is utilized (Page 890, Column 1; Page 893, Column 2).
As such, Yuan et al disclose that the SIRM technique involves the delivering and patterning of human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts onto a two-dimensional polydimethylsiloxane (PDMS) SIRM using microfluidic channels, and then releasing the SIRM to roll up – or self-fold – into a three-dimensional tube (Page 890, Columns 1-2; Page 891, Columns 1-2; Pages 893-894, Fabrication; Page 895, Cell Culture and Staining; Figures 1-2, 5).
Yuan et al further disclose that the two ends of the SIRM are fixed to a surface via commercial tape, wherein one side of the tape is cut to allow the SIRM to self-fold (Page 891, Column 1; Page 892, Column 1).
Yuan et al further disclose that the biomimetic tubular structures can be utilized to model any tubular tissue via the customization of the seeded cells, including the trachea, blood vessels, lymph vessels, and intestines (Page 890, Columns 1-2).
Yuan et al do not disclose that the pre-stretched PDMS membrane is provided over a sacrificial layer, as required by instant claim 28.
Livermore-Clifford et al, however, disclose the formation of 3D engineered tissues by providing a 2D scaffold material (Abstract).
As such, Livermore-Clifford et al disclose a self-folding PDMS structure, wherein the 2D PDMS sheet is provided over a sacrificial layer, seeded with cells, and then actuated into self-folding via the dissolution of the sacrificial layer (Paragraphs [0036], [0042], [0059]-[0060]).
Therefore, it would have been prima facie obvious to have modified the method of Yuan et al such that the PDMS membrane is provided over a sacrificial layer, as detailed in Livermore-Clifford et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize a sacrificial layer, as it allows for the release of the PDMS membrane with little to no external contact (Livermore-Clifford et al: Paragraph [0042]), and would have had a reasonable expectation of success based on the combined disclosures of Yuan et al and Livermore-Clifford et al. Furthermore, since the disclosures of both Yuan et al and Livermore-Clifford et al are concerned with the generation of self-folded biomimetic vessels, there will be minimal adaptation required between the two methods. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Livermore-Clifford et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein a two-dimensional PDMS SIRM is patterned (claim 87) and provided over a sacrificial layer, seeded with human endothelial cells, smooth muscle cells, and fibroblasts, and then allowed to self-fold into a three-dimensional tube via the dissolving of the sacrificial layer (claim 80). As the biomimetic vessel of Yuan et al is substantially identical to the instantly claimed biomimetic in vitro model of a pulmonary vessel, this therefore renders obvious the method of instant claim 28. See MPEP § 2112.01(I).
Regarding claims 81-82: Following the discussion of claim 28, Yuan et al further disclose that the PDMS membrane has a thickness of about 10 microns (Figure S2). This therefore reads on the method of the instant claims.
Regarding claim 83: Following the discussion of claim 28, Yuan et al further disclose that the inner diameter – or lumen – of the vessel is from about 100 microns to 2 mm (Page 891, Column 2). As the lumen diameter range overlaps with the claimed range of 25 microns to 200 microns, this therefore renders obvious the method of the instant claim. See MPEP § 2144.05.
Regarding claim 86: Following the discussion of claim 28, Yuan et al further discloses that fibronectin is added to promote cell adhesion of the patterned smooth muscle cells to the pre-stretched PDMS membrane (Page 894, Column 2; Figure 4). This therefore reads on the method of the instant claim.
Claims 28, 79-83, and 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Livermore-Clifford et al (US 2016/0032239 A1), and further in view of Fan et al (ACS Appl Mater Interfaces, 2016).
The discussion of Yuan et al as modified by Livermore-Clifford et al regarding claim 28 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Livermore-Clifford et al render obvious claims 28, 80-83, and 86-87. Fan et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 79: As aforementioned in the discussion of claim 28 above, Yuan et al as modified by Livermore-Clifford et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein a two-dimensional PDMS SIRM is provided over a sacrificial layer, seeded with human endothelial cells, smooth muscle cells, and fibroblasts, and then allowed to self-fold into a three-dimensional tube via the dissolving of the sacrificial layer.
Livermore-Clifford et al further disclose that the sacrificial layer can be sucrose or polyvinyl alcohol (PVA) (Paragraph [0060]).
The combination of Yuan et al and Livermore-Clifford et al fail to teach that the sacrificial layer is dissolvable in culture media, as required by instant claim 79.
Fan et al, however, disclose the formation of self-folded polymeric structures, wherein PVA is utilized as a sacrificial layer and is water-soluble (Pages 33351, 33355-33356, 33358, 33361; Figure 11).
Therefore, it would have been prima facie obvious to have modified the method of Yuan et al and Livermore-Clifford et al such that the sacrificial layer is a water-soluble PVA, as detailed in Fan et al. One of ordinary skill in the art before the effective filing date of the instant invention would have been motivated to utilize a water-soluble sacrificial layer, as it allows for the dissolution of the sacrificial layer with simple mediums – including culture media, and would have had a reasonable expectation of success given the disclosures of Livermore-Clifford et al and Fan et al. Furthermore, since the disclosures of Yuan et al, Livermore-Clifford et al, and Fan et al are concerned with the generation of self-folded biomimetic vessels, there will be minimal adaptation required between the methods. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Livermore-Clifford et al and Fan et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein the sacrificial layer is water-soluble PVA that is capable of dissolving in culture media. This therefore renders obvious the method of the instant claim.
Claims 28, 80-84, and 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Livermore-Clifford et al (US 2016/0032239 A1), and further in view of Miklas et al (US 2016/0282338 A1, of record) and Sicard et al (J Mech Behav Biomed Mater, 2017).
The discussion of Yuan et al as modified by Livermore-Clifford et al regarding claim 28 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Livermore-Clifford et al render obvious claims 28, 80-83, and 86-87. Miklas et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Sicard et al is considered prior art under 35 USC 102(a)(1), with an electronic publication date of 31 May 2017.
Regarding claim 84: As aforementioned in the discussion of claim 28 above, Yuan et al as modified by Livermore-Clifford et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein a two-dimensional PDMS SIRM is provided over a sacrificial layer, seeded with human endothelial cells, smooth muscle cells, and fibroblasts, and then allowed to self-fold into a three-dimensional tube via the dissolving of the sacrificial layer.
The combination of Yuan et al and Livermore-Clifford et al fail to teach that the vessel wall modulus is about 0.1 to 15 kPa, as required by instant claim 84.
Miklas et al, however, disclose an engineered three-dimensional tissue comprised of layered smooth muscle cells and endothelial cells that recapitulates at least the overall tubular geometry, including turns and folds, and cellular alignment of an in vivo vessel (Paragraphs [0504]-[0505], [0511], [0514], [0681]).
Miklas et al further disclose that the engineered three-dimensional tissue has an elastic modulus that matches the tissue in which it is replacing and/or mimicking (Paragraph [0773]).
With that, Sicard et al disclose that the elastic modulus of human pulmonary arterial walls is about 5 kPa, with fluctuations in the measurement depending on the tissue thickness (Pages 122-123; Figures 3C-D).
Therefore, it would have been prima facie obvious to have modified the method of forming a biomimetic tubular vessel of Yuan et al and Livermore-Clifford et al such that the elastic modulus of the biomimetic tubular vessel matches the natural elastic modulus of human pulmonary arteries, as detailed in Miklas et al and Sicard et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to generate a biomimetic pulmonary vessel model having similar mechanical properties as the native tissue, as it simulates a native physiological environment for both in vitro and in vivo applications (Miklas et al: Paragraph [0773]). Furthermore, the ordinary artisan would have had a reasonable expectation of success since the biomimetic vessel of Yuan et al is highly tunable and it would not have been outside the skillset of the ordinary artisan to modulate the elastic modulus of the PDMS membranes. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Livermore-Clifford et al, Miklas et al, and Sicard et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein the self-folded three-dimensional tubular structure has a vessel wall modulus of about 5 kPa. This therefore renders obvious the method of the instant claim.
Claims 28, 80-83, and 85-87 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al (Adv Mater, 2012) in view of Livermore-Clifford et al (US 2016/0032239 A1), and further in view of Imperial College London (YouTube, 2016, of record).
The discussion of Yuan et al as modified by Livermore-Clifford et al regarding claim 28 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Yuan et al as modified by Livermore-Clifford et al render obvious claims 28, 80-83, and 86-87. Imperial College London is considered prior art under 35 USC 102(a)(1).
Regarding claim 85: As aforementioned in the discussion of claim 28 above, Yuan et al as modified by Livermore-Clifford et al render obvious a method of forming a biomimetic tubular models of a vessel, wherein a two-dimensional PDMS SIRM is provided over a sacrificial layer, seeded with human endothelial cells, smooth muscle cells, and fibroblasts, and then allowed to self-fold into a three-dimensional tube via the dissolving of the sacrificial layer.
Yuan et al further disclose that the biomimetic tubular structures can be utilized to model any tubular tissue via the customization of the seeded cells, including the trachea, blood vessels, lymph vessels, and intestines (Page 890, Columns 1-2).
Yuan et al do not disclose that the human smooth muscle cells and endothelial cells are patterned human pulmonary artery smooth muscle cells (HPASMC) and human pulmonary endothelial cells (HPMEC), as required by instant claim 85.
Imperial College London, however, disclose a three-dimensional model of a lung blood vessel on a microchip, wherein the lung blood vessel is comprised of human patient-derived pulmonary smooth muscle cells and endothelial cells (Page 2; Page 4, 1:06-1:26, 1:27-1:41, 1:52-2:08).
Therefore, it would have been prima facie obvious to have modified the method of forming a biomimetic tubular vessel of Yuan et al and Livermore-Clifford et al to generate a biomimetic pulmonary vessel using human patient-derived pulmonary artery smooth muscle cells and endothelial cells, as detailed in the video produced by Imperial College London. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to generate a biomimetic pulmonary vessel model, as it allows for the ability to investigate changes that happen in the diseased lung blood vessels and test individual patient’s responses to drugs in a highly controlled environment (Imperial College London, Page 5, 2:09-2:23). Furthermore, the ordinary artisan would have had a reasonable expectation of success based on the disclosure of Imperial College London combined with the protocols outlined in Yuan et al – especially as both are concerned with the generation of vessel models. See MPEP § 2143(I)(G).
Consequently, Yuan et al as modified by Livermore-Clifford et al and Imperial College London render obvious a method of forming a biomimetic tubular models of a vessel, wherein discrete layers of human-derived pulmonary artery smooth muscle cells, endothelial cells, and fibroblasts are patterned onto the pre-strained PDMS membrane. This therefore render obvious the method of the instant claim.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
Prosecution Insights