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 .
Election/Restrictions
Applicant’s election without traverse of Group II (claims 14-19) in the reply filed on Nov. 12, 2025 is acknowledged. Claims 1-13 and 20-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The claim set filed Dec. 7, 2022 is the most recent claim set.
Claims 1-13 and 20-22 are withdrawn as being drawn to non-elected inventions. Claims 14-19 are examined on their merits below.
Priority
The application claims priority to provisional applications 63/287254, filed Dec. 8, 2021 and 63/399494, filed Aug. 19, 2022; as such the earliest possible priority date is Dec. 8, 2021.
Information Disclosure Statement
The information disclosure statement filed May 4, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, this IDS has been considered by the examiner.
The information disclosure statement filed Aug. 22, 2025* fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
*Please note that IDSs filed after Jan. 19, 2025 must be filed with an IDS size fee assertion form and the appropriate fee, if applicable.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of endothelial cells with forskolin and fingolimod-phosphate, when the concentration of forskolin is 40 µM and FYTP is 50 µM or 5 µM (Figure 5), it does not reasonably provide enablement for any amount of fingolimod-phosphate being present in conjunction with any amount of forskolin and functioning as a barrier agonist compound. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant
by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of
experimentation is permissible, if it is merely routine, or if the specification in
question provides a reasonable amount of guidance with respect to the direction
in which experimentation should proceed to enable the determination of how to
practice a desired embodiment of the claimed invention.
PPG V. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
1 As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation."
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1) the nature of the invention,
2) the breadth of the claims,
3) the state of the prior art,
4) the predictability or unpredictability of the art,
5) the relative skill of those in the art,
6) the amount of direction or guidance provided,
7) the presence or absence of working examples,
8) the quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833,839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1) The nature of the invention and 2) the breadth of the claims
The claims are drawn methods of improving production of lung tissue from endothelial cells, the endothelial cells (ECs) being cultured in cell culture medium, where the improvement includes contacting the cultured ECs with at least two barrier agonist compounds including forskolin and fingolimod-phosphate, and maintaining the ECs in the cell culture medium for a sufficient time to enable strengthening of a vascular barrier. A wherein clause indicates that the strengthening leads to a reduction in vascular leak.
Thus, the claims taken together with the specification imply that Applicant is claiming that any amount of fingolimod-phosphate will work in conjunction with forskolin as a barrier agonist in the claimed method - that is, specifically that administering any amount of fingolimod-phosphate will function, in conjunction with forskolin, as a barrier agonist when contacting the cultured endothelial cells, thereby strengthening the vascular barrier of the cells.
3) the state of the art, 4) unpredictability of the art and 5) the relative skill
of those in the art
The relative skill of those in the art is high, generally that of a PhD in biochemistry or a research physician.
That factor is outweighed however by the unpredictable nature of the art.
The prior art teaches that cAMP and S1P regulate barrier function. For example, Vandenbroucke et al. (Ann N.Y. Acad. Sci, 2008, cited IDS filed on May 4, 2023), a review article, summarizes the signaling mechanisms regulating endothelial permeability which includes both S1P internalization and increased cAMP levels (Figure 3). See also Birukova et al. (Microvascular Research, 2010, cited IDS filed on May 4, 2023), which teaches that RAC GTPase plays a role in the enhancement of lung vascular barrier through increasing cAMP; more specifically, treatment of human pulmonary artery endothelial cells (HPAECs) with a stable cAMP analog, 8Br-cAMP, activates PKA, Rap 1 and Rac, and attenuates EC barrier dysfunction (Figures 1-2).
Butler et al. (Prostaglandin Other Lipid Mediat, 2004, cited IDS filed on May 4, 2023) teach that HUVECs incubated with forskolin have an increase in cAMP production and addition of S1P and FTY720P to the media with forskolin significantly reduced the amount of cAMP produced (Figure 5). The reduction of cAMP production was dependent on the concentration of FTY720 used (pg. 41, 3.4). Thus the art teaches that forskolin leads to an increase in cAMP levels, and S1P agonists (such as FTY720P) decrease cAMP levels. cAMP is known to have a protective effect on barrier function (see e.g. Birukova et al. (Microvascular Research, 2010, cited IDS filed on May 4, 2023). With this information, it seems counter-intuitive to treat the cells with forskolin and FTY720P to improve barrier function. Butler et al. (Prostaglandin Other Lipid Mediat, 2004, cited IDS filed on May 4, 2023) suggest that the effect of fingolimod phosphate on cAMP levels may be concentration dependent
The examples provided in the application show an improvement in cell barrier function upon treatment of endothelial cells with forskolin and fingolimod-phosphate when compared to FSK treated or untreated cells, when the concentration of forskolin is 40 µM and FYTP is 50 µM or 5 µM (Figure 5).
Thus, the person of ordinary skill in this art has an understanding that increased cAMP will improve barrier function, that forskolin increases cAMP and improves barrier function and that FYTP generally inhibits the increase of cAMP provided by forskolin. That person does not have an understanding that any amount of forskolin and any amount of FYTP will improve barrier function. There is no way for one skill in the art to know, a priori, which concentrations of both forskolin and FYTP will increase barrier permeability with a reasonable expectation of results. Thus, the state of the prior art does not support the broad scope of the claims.
6) the amount of direction and guidance provided and 7) the presence
and absence of working examples
The specification indicates that any amount of forskolin and FYTP together will improve barrier function. (paras. [0009], [0011], [0074]). The examples provided in the application show an improvement in cell barrier function upon treatment of endothelial cells with forskolin and fingolimod-phosphate when compared to FSK treated or untreated cells, when the concentration of forskolin is 40 µM and FYTP is 50 µM or 5 µM. (Figure 5).
8) The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and
in the absence of experimental evidence commensurate in scope with the claims,
the skilled artisan would not accept the assertion that treatment of endothelial cells with any amount of fingolimod-phosphate being present in conjunction with any amount of forskolin will function as a barrier agonist compound, as inferred in the claims and contemplated by the
specification.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable." (42 USPQ 2d 1001, Fed. Circuit 1997).
To practice the invention of the instant claims required undue experimentation due to unpredictability in how forskolin and FYTP will behave when both present.
As Butler et al. (Prostaglandin Other Lipid Mediat, 2004, cited IDS filed on May 4, 2023) explain, HUVECs incubated with forskolin have an increase in cAMP production and addition of S1P and FTY720P to the media with forskolin significantly reduced the amount of cAMP produced (Figure 5). The reduction of cAMP production was dependent on the concentration of FTY720 used (pg. 41, 3.4). Thus the art teaches that forskolin leads to an increase in cAMP levels, and S1P agonists (such as FTY720P) decrease cAMP levels. cAMP is known to have a protective effect on barrier function (see e.g. Birukova et al. (Microvascular Research, 2010, cited IDS filed on May 4, 2023).
To practice the invention of the instant claims requires undue experimentation due to the unpredictability of the presence of forskolin and FYTP together, which generally is understood to counteract the effects of cAMP, except when within certain concentrations, as taught by the specification. The amount of experimentation required in order to determine which of these ranges will work to promote the endothelial barrier is large due to this contradictoary understanding. To determine if the combination of forskolin and FTTP will work to increase the endothelial barrier would require inventive effort and extensive experimental burden.
In light of the above discussion, the instant claims do not comply with the
enablement requirement of 35 U.S.C. § 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 14-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 14 recites the term “at least two barrier agonist compounds”. The term “barrier agonist compound” is indefinite as is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Para. [0035] of the specification appears to give a definition: “As used herein, the term ‘barrier agonist compound’ refers to any compound that can enhance a vascular barrier of endothelial cells, as determined by, for example, a reduction in vascular leak. Barrier agonist compounds may enhance a vascular barrier of endothelial cells through one or more overlapping or distinct mechanisms. As a nonlimiting example, generally, barrier agonists may enhance the endothelial expression of tight and adherens junctional proteins, which help to regulate passage of fluid and molecules from the bloodstream to the underlying lung tissue.”
The examples given are non-limiting. The definition given, while appearing to be complete, does not resolve the indefiniteness, as it is unclear exactly how “indirect” the effect of enhancing a barrier of endothelial cells is. The reduction of a vascular leak is not recited as a requirement; rather an example of something that would demonstrate an enhanced vascular barrier. Additionally, in the examples given are such broad and vaguely recited components such as “compounds…that promote increased production of cyclic adenosine monophosphate” this could be as far reaching as dietary compounds such as resveratrol and oleanolic acid, glucagon, prostaglandins, neurotransmitters such as adenosine, insulins, androgens and many others, as increased production of this secondary messenger is far reaching. If reduction of vascular leak is not required for the compound to be used as a “barrier agonist compound,” then how exactly would one of ordinary skill in the art determine how indirect a compound can be that enhances an endothelial cell barrier? The examples also indicate that direct or indirect activators of the signaling enzyme Rac1 are “barrier agonist compounds.” This includes another extensive list (insulin, androgens, collagen, cyclic GMP, protein kinase C, hydrogen peroxide, fibronectin, and more), and it is not clear exactly how indirect the activation of Rac1 can be and still be included as a “barrier agonist compound.” While the term “barrier agonist compound” can be interpreted broadly, it is not clear how far those boundary lines would reach and what compounds would be included and which ones would be excluded as being too indirect or not enough of an activator, etc.
The specification indicates that “barrier agonist compounds may include one or more compounds that promote increased expression of endothelial cell-cell junctions, that promote increased production of cyclic adenosine monophosphate, that promote increased production of adherens junction proteins (e.g., VE-Cadherin), or that promote increased production of tight junction proteins (e.g., ZO-1, JAM-A, Claudin-5, Occludin). In some preferred embodiments, a method of producing endothelial cells may include contacting the endothelial cells with at least two barrier agonist compounds, wherein the at least two barrier agonist compounds include forskolin and fingolimod-phosphate. In some embodiments, the barrier agonist compounds may further include methylprednisolone.” (para. [0009]. Para. [0040] recites more non-limiting examples of barrier agonist compounds: “Non-limiting examples of barrier agonist compounds include: adenylyl cyclase activators; activators of Sphingosine-1-phosphate (S1P) receptor internalization; direct or indirect activators of the signaling enzyme Rac1; direct or indirect inducers of tight junction protein (e.g., ZO-1, JAMA, Claudin-5, and Occludin) expression, and direct or indirect inducers of adherens junction protein (e.g., VE-Cadherin) expression.”
Claims 15-19 do not resolve this indefiniteness, as, even thought claim 15 recites two specific compounds, forskolin and fingolimod-phosphate, additional “barrier agonist compounds” could be included and would still be indefinite. Claims 16-19 depend from claim 15 and also do not resolve the indefiniteness of additional barrier agonist compounds that could be present.
For the purposes of examination, the term “barrier agonist compounds” is limited to those enumerated by applicants in the specification, either by name or by class, excluding those that are “indirect” activators and inducers.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren et al. (U.S. Patent No. 10,731,135, cited in IDS filed on May 5, 2023).
Independent claim 14, written as a Jepson claim, is directed to a method of improving production of lung tissue from endothelial cells, the endothelial cells (ECs) being cultured in cell culture medium, where the improvement includes contacting the cultured ECs with at least two barrier agonist compounds, and maintaining the ECs in the cell culture medium for a sufficient time to enable strengthening of a vascular barrier. A wherein clause indicates that the strengthening leads to a reduction in vascular leak.
Ren et al. teach a method of rat lunch regeneration, including seeding endothelial cells (HUVEC) into decellularized rat lungs and culturing them in cell culture medium (angiogenic medium – supplemented medium 199) for 6 days, then culturing the ECs in stabilization medium, which included proangiogenic factors, forskolin and hydrocortisone (“two barrier agonist compounds”) which promotes vascular stabilization and barrier function, as seen by lack of leakage (claim 1, Figure 7A-B).
Conclusion
No claims are allowed.
Claim 19 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The closest prior art, As Butler et al. (Prostaglandin Other Lipid Mediat, 2004, cited IDS filed on May 4, 2023) teaches HUVECs incubated with forskolin have an increase in cAMP production and addition of S1P and FTY720P to the media with forskolin significantly reduced the amount of cAMP produced (Figure 5). The reduction of cAMP production was dependent on the concentration of FTY720 used (pg. 41, 3.4).
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/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634