REOPENING OF PROSECUTION AFTER APPEAL BRIEF
In view of the Appeal Brief filed on 4/2/2026, PROSECUTION IS HEREBY REOPENED. New grounds of rejection set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
/PETER PARAS JR/ Supervisory Patent Examiner, Art Unit 1632
DETAILED ACTION
Claims 1-17 are pending and examined herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20220106572A1, Published 4/7/2022.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) are drawn to a blood brain barrier, said model comprising six cell types of: astrocytes, pericytes, endothelial cells, neuronal cells, oligodendrocytes and microglia, wherein said model is in the form of a spheroid comprising said six cell types. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following:
Independent claim 1 is drawn to an in vitro model of a blood brain barrier (BBB), said model comprising six cell types of: astrocytes, pericytes, endothelial cells, neuronal cells, oligodendrocytes and microglia, wherein said model is in the form of a spheroid comprising said six cell types.
Claim interpretation: Under the broadest reasonable interpretation, the terms of the claim are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art. See MPEP 2111. As such, the broadest reasonable interpretation of claim 1 is a natural occurring BBB.
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP 2106.03. Here, the claim recites a BBB comprising six cell types. Because a BBB is a composition of matter, the claims falls within a statutory category. (Step 1: YES)
Step 2A, Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP 2106.04(II) and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. Because claim 1 recites a nature-based product limitation (cells), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. MPEP 2106.04(c)(I). MPEP 2106.04(c)(I)(A). The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. MPEP 2106.04(c)(II).
Here, the closest natural counterpart to the BBB of claim 1 is a naturally occurring BBB. The art, as exemplified in Sá-Pereira et al. (Col Neurobiol 45, 327–347 (2012)., previously cited) teaches the blood–brain barrier (BBB) is a highly specialized system that controls the exchanges between the blood and the central nervous system (CNS). This barrier shields the CNS from toxic substances in the blood and provides nutrients to CNS, thus playing an essential role in the maintenance of homeostasis. The anatomical basis of the BBB is formed by the endothelial cells of brain microvasculature, with elaborated tight and adherens junctions, which together with pericytes, the basement membrane, and astrocytes, as well as neurons, microglia and oligodendrocytes form the neurovascular unit (Pg. 327, Col. 1). Sá-Pereira et al. (---- Mol Neurobiol. 2012 Apr;45(2):327-47.) provides the anatomical structure of the BBB in the attached figure.
PNG
media_image1.png
946
714
media_image1.png
Greyscale
Note Fig. 2B is an electron micrograph of a capillary cross-section in a rat brain. Further note the shape of the capillary cross-section in the rat brain of Fig. 1B is a spheroid.
Accordingly, the claim recites a judicial exception, and the analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55. And although claims 11 and 12 are drawn to methods of using the BBB of claim 1, the steps recited therein merely narrow the nature-based product and do not add significantly more beyond the judicial exception. Thus, the claim fails to recite additional elements beyond the judicial exception. (Step 2A: YES)
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. Claim 6 recites percentages of the cells of claim 1. Although these percentages do not appear in a naturally occurring BBB, the percentages of the cells of claim 1 do not amount to significantly more than the recited exception. This is because the specification does not disclose that the claimed percentages imbued a new property onto the BBB.
In Funk Brothers, the Courts held the claimed bacterial mixture ineligible because each species of bacteria in the mixture continued to have “the same effect it always had”, i.e., it lacked markedly different characteristics. Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948), discussed in Myriad Genetics, 133 S. Ct. at 2117 (explaining that the bacterial mixture of Funk Brothers “was not patent eligible because the patent holder did not alter the bacteria in any way”). While not discussed in the opinion, it is noted that several of the claims held ineligible in Funk Brothers recited specific amounts of the bacterial species in the mixture, e.g., claims 6, 7 and 13. Funk Brothers, 333 U.S. at 128 n.1. These amounts do not appear in nature. (Step 2B: NO). Because the percentages of claim 6 do not imbue any new property onto the BBB of claim 1, the claim, as a whole, is not eligible.
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.
Prior Art Rejection 1
Claim(s) 1, 3-8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Hsou et al. (PLoS One. 2014 Sep 4;9(9):e106346) in view of Urich et al. (Sci Rep 3, 1500 (2013); Ref. 26 in IDS filed 12/9/21).
Hsou et al. teach the neurovascular unit (NVU) is the quintessential organizational principle of functional brain tissue. Hsou teaches signaling between the vascular and neural cells is a key physiological process regulating the interaction between peripheral circulation and brain activity. At the interface of the vascular and neural compartments is the blood-brain barrier (BBB) that limits the access of molecules and peripheral cells to the brain. In the healthy brain, neuronal and glial activity will influence vascular function by neurovascular coupling to regulate their energetic demands by maintaining tissue oxygenation and nutrient influx. In the case that this energetic demand is not met, a rapid physiological response to hypoxia (i.e. lack of sufficient oxygenation) induces an angiogenic cascade that aims to restore tissue oxygenation. Hsou teaches that in stroke, where blood flow to brain tissue is blocked for protracted periods of time, cells die. Hsou also adds that NSCs injected into a stroke cavity with bioscaffolding by themselves do not lead to re-vascularization,, a common problem observed in tissue engineering. Strategies aimed at modulating the vascular response following a stroke or NSC transplantation, vascularization of engineered tissues, as well as inhibition of angiogenesis in brain tumors are grounded on a thorough understanding of the dynamic paracrine, autocrine and juxtacrine interactions in the NVU. However, parceling out these interactions in vivo, especially in humans, is extremely challenging. Therefore, Hsou notes that the development of in vitro models that afford a high level of experimental control and reproducibility is required to complement in vivo studies (Pg. 1, Col. 1- Pg. 2, Col. 2).
Towards this end, Hsou et al. co-cultured human (as in claim 6, in-part) neural stem cells (hNSC) (Pg. 2, Col. 1) with human (as further in claim 6) adult cerebral microvascular endothelial (as in claim 1, in-part) cell line (hCMEC) (as in claim 7 and claim 8) (Pg. 2, Col. 2, para. 1). Hsou teaches hCMECs organized into a 3 dimensional structure of 8–10 hCMECs in width (Figure 6A) with diameters ranging from 8–50 µm. hNSCs covered the coverslip with hCMECs assembling and rising above these into vascular like structures (VLS) (Figure 6B). hNSCs differentiated into neurons (MAP2+ cells) (as in claim 1, in-part), oligodendrocytes (GalC+ cells) (as in claim 1, in-part) and astrocytes (GFAP+ cells) (as in claim 1, in-part) (Pg. 11, Col. 1, para. 1). Hsou teaches the phenotypic consequence of coculturing predominately affected neuronal differentiation for hNSCs, whereas in hCMECs some intercellular junction proteins (as in claim 10, in-part) (Pg. 11, Col. 1, para. 1; Fig. 7) were reduced reflecting the state of VLS maturation (Pg. 2, Col. 2, para. 2; Abstract).
Hsou teaches the formation of VLS in hCMEC/hNSC coculture suggests that these two cell types provide the sufficient conditions to produce an endothelial morphogenesis. Nevertheless, Hsou teaches that it is known that additional cell types, such as pericytes and microglia, populate the NVU in the brain. Specifically, Hsou teaches pericytes have been associated with functions of the BBB with measurements of trans-endothelial electrical resistance being required to determine barrier functions. To serve as a “complete” model of the BBB, it would be essential that the formed capillaries can be perfused to determine if indeed a lumen can be formed and if there is transfer of molecules from the vascular to the “neural” compartment. Hsou adds that microglia have also been reported to be involved in the formation of novel blood vessels and are a key modulator of signaling that involves inflammatory cytokines. Therefore, Hsou concludes that to truthfully model the NVU to study, for instance, signaling in hypoxia, it is essential to further expand the assay described here to also include these types of cells. Thus, given these teachings in Hsou et al., one of ordinary skill in the art would have found it prima facie obvious to include pericytes (as in claim 1, in-part) and microglia (as further in claim 1) in the in vitro BBB model of Hsou as Hsou makes clear these cells are essential (Pg. 15, Col. 1, para. 1-2).
However, Hsou fails to teach the model is in the form of a spheroid (as further in claim 1).
Before the effective filing date of the claimed invention, Urich et al. studied BBB formation in a 3-dimensional multicellular spheroid (as further in claim 1) system of human primary brain (microvascular) endothelial cells (hpBECs) (as in claim 3, claim 6, claim 7 and claim 8), human primary pericytes (hpPs) (as in claim 5 and claim 6) and primary astrocytes (hpAs) (as in claim 4 and claim 6) (Pg. 7, ‘Methods’). Urich et al. show that hpBECs, hpPs and hpAs spontaneously self-organize into a defined multicellular structure which recapitulates the complex arrangement of the individual cell types in the BBB structure. Urich notes that the 3D hanging-drop spheroid model was adopted in order to study the role of BECs, pericytes and astrocytes in BBB assembly because it is less well understood (Abstract; Pg. 6, Col. 1).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Hsou et al., wherein Hsou teaches an in vitro BBB model comprising cells of the NVU, specifically astrocytes, neurons, pericytes, oligodendrocytes, microglia and endothelial cells, with teachings of Urich et al., wherein Urich teaches an in vitro BBB model in the form of a spheroid. The skilled artisan would have found it prima facie obvious to do because Hsou specifically teaches that although the VLS expanded beyond the monoculture during endothelial morphogenesis in their in vitro model, this cannot truly be considered a 3 dimensional environment and as the NVU in the brain is a 3D environment. Hsou therefore suggests that a further advance would be to create an artificial 3D environment in vitro (Pg. 15 ‘Limitations of the assay’). A reasonable expectation of success is present given Urich’s success in deriving a 3D hanging drop spheroid model to study the BBB.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious
Prior Art Rejection 2
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Hsou et al. (PLoS One. 2014 Sep 4;9(9):e106346) in view of Urich et al. (Sci Rep 3, 1500 (2013); Ref. 26 in IDS filed 12/9/21) as applied to claims 1, 3-8 and 11 above, and further in view of Lippmann et al. (J Neurochem. 2007;101:555–565.).
The teachings of Hsou et al. and Urich et al. are relied upon as detailed above. However, neither Hsou et al. nor Urich et al. teach the in vitro BBB model comprises primary neuronal or neuronal progenitor cells (as in claim 2).
Before the effective filing date of the claimed invention, Lippmann et al. taught blood-brain barrier (BBB) models are often used to investigate BBB function and screen brain-penetrating therapeutics, but it has been difficult to construct a human model that possesses an optimal BBB phenotype and is readily scalable. To address this challenge, Lippmann developed a human in vitro BBB model comprising brain microvascular endothelial cells (BMECs), pericytes, astrocytes and neurons. Lippmann teaches retinoic acid (RA) was used to substantially enhance BBB phenotypes in human pluripotent stem cell (hPSC)-derived BMECs, particularly through adherens junction, tight junction and multidrug resistance protein regulation. RA-treated hPSC-derived BMECs were subsequently co-cultured with primary human brain pericytes and human astrocytes and neurons derived from human neural progenitor cells (NPCs) (as in claim 2) to yield a fully human BBB model that possessed significant tightness as measured by transendothelial electrical resistance (~5,000 Ωxcm2). Overall, Lippmann teaches this scalable human BBB model may enable a wide range of neuroscience studies (Abstract; Pg. 5 Col. 1-Col. 2).
When taken with the teachings of Hsou et al. in view of Urich et al., wherein the combination teaches a BBB model comprising primary astrocytes, primary pericytes, primary endothelial cells, neuronal cells, oligodendrocytes and microglia in a spheroid formation, one of ordinary skill in the art would have found it prima facie obvious to incorporate the teachings of Lippmann et al. who used neurons derived from human neural progenitor cells (NPCs) to recapitulate an in vitro BBB model. The skilled artisan would have found it prima facie obvious to do so because Lippmann teaches the use of NPCs along with brain microvascular endothelial cells, primary pericytes and primary astrocytes, yielded a fully human BBB model that possessed significant tightness as measured by transendothelial electrical resistance and was readily scalable (see Abstract of Lippmann). Thus, for the same benefits, the combination would have been prima facie obvious.
The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation.
Prior Art Rejection 3
Claims 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hsou et al. (PLoS One. 2014 Sep 4;9(9):e106346) in view of Urich et al. (Sci Rep 3, 1500 (2013); Ref. 26 in IDS filed 12/9/21) as applied to claims 1, 3-8 and 11 above, and further in view of Prabhakarpandian et al. (PgPub US20110104658A1, Published 5/5/2011).
The teachings of Hsou et al. and Urich et al. are relied upon as detailed above. However, neither Hsou et al. nor Urich et al. teach a microfluidic device comprising an in vitro BBB model (as in claim 14).
Before the effective filing date of the claimed invention, Prabhakarpandian et al. taught screening drug candidates and drug delivery vehicles for their abilities to cross from the blood into the brain through the Blood-Brain Barrier (BBB) is an important aspect of the development of Central Nervous System (CNS) therapeutics. Available in vitro BBB assays use incubation chambers separated by a filter membrane designed to mimic the BBB. Such devices do not reproduce physiological microenvironmental parameters, shear stress induced by blood flow and transport effects caused by phenotypic changes in the microvasculature. In vivo BBB assays involve small animal models that are expensive, lengthy and difficult to scale up for high throughput screening. Existing in vitro and in vitro BBB assays do not provide cost- and time-effective formats for real-time visualization or quantitation of the transport of drug and drug delivery candidates across the BBB (Pg. 1, para. 6).
Thus, to remedy this deficiency, Prabhakarpandian teaches the Synthetic Microvascular Blood-Brain Barrier (SyM-BBB), comprising a plastic, disposable and optically clear microfluidic chip (as in claim 14) with embedded microfluidic flow channels having geometric features and sizes similar to those found in vivo (Pg. 1, para. 9). Prabhakarpandian teaches for permeability studies, tagged (e.g., fluorescently labeled) drug and/or drug delivery vehicle candidates are introduced into an apical side of the SyM-BBB. The movement of candidates from the flow channels through the layer(s) of cells and into the tissue space(s) is measured using one or more standard imaging techniques. The measured permeabilities of candidates may be used to objectively compare drugs in their ability to cross the BBB (as in claim 11 and claim 15) (Pg. 1, para. 11). In addition, Prabhakarpandian teaches the integrity of the blood-brain barrier may be assessed by monitoring the formation of tight-junctions between endothelial cells. Prabhakarpandian teaches genes that are indicative of the formation of tight junctions include ZO-1, claudin 1 and 5 and P-glycoprotein (as in claim 12, claim 13, claim 16 and claim 17) (Pg. 4, para. 45).
When taken with the teachings of Hsou et al. in view of Urich et al., wherein the combination teaches a BBB model comprising primary astrocytes, primary pericytes, primary endothelial cells, neuronal cells, oligodendrocytes and microglia in a spheroid formation, one of ordinary skill in the art would have found it prima facie obvious to incorporate the teachings of Prabhakarpandian et al., wherein Prabhakarpandian teaches a microfluidic device suitable for screening compounds having an effect on an in vitro derived BBB. The skilled artisan would have found it prima facie obvious to house the BBB of Hsou in view of Urich in the microfluidics device of Prabhakarpandian because Prabhakarpandian teaches that compared with static well-plate incubation assays as well as the other available in vitro platforms, the SyM-BBB accurately reproduces in vivo size and flow microenvironments and enables a physiologically-relevant testing system for drug screening and delivery experiments (see Prabhakarpandian at Pg. 1, para. 8).
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TITILAYO MOLOYE whose telephone number is (571)270-1094. The examiner can normally be reached Working Hours: 5:30 a.m-3:00 p.m. M-F. Off first Friday of biweek.
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, Peter Paras can be reached on 571- 272-4517. 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.
/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
Prosecution Insights