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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/GB/2021/050841 (filed 4/6/2021). Acknowledgment is made of Applicants’ claim for priority to foreign application GB2005154.6 (filed 4/7/2020). A certified copy of the foreign priority application is present in the application file.
Election/Restrictions
An initial restriction requirement was mailed on 6/16/2025. In a response received on 9/16/2025 Applicants elected Group 1, drawn to a method of making a 3-D model for alveolar tissue. This Grouping also included claims drawn to the 3D model, per se. The election was treated as an election without traverse. Amendments to the claims presented on 9/16/2025 negated the election of species requirements.
A second restriction requirement was mailed on 10/6/2025, setting forth additional election of species requirements. Applicants’ response of 12/2/2025 was fully responsive. However, upon reconsideration, all previously imposed requirements to elect a single species of the elected invention are withdrawn. Claims 1, 2, 4, 7, 9, 10, 12, 13, 15, 17-20, 22, 24, 25, 29-32, and 61-64 are pending, all read on the elected invention, and all have been considered on the merits.
Claim Interpretation
In claim 2, the requirement that “all cells are immortalized mammalian cell lines” is interpreted as meaning both the alveolar type I epithelial cells and the alveolar macrophage-like cells are immortalized mammalian cell lines.
In claim 4, the requirement that the first/second compartment be “configured” to be exposed to an air-liquid interface (ALI) or to be submerged in culture medium, respectively, is interpreted as meaning that the model is physically capable of having the first compartment be exposed to an ALI and the second compartment be submerged ink culture medium.
In claim 7, as no physical characteristics are required, the denotation of the first compartment as the “apical compartment”, the side of the membrane facing the first compartment being “an apical side”, the second compartment being “a basolateral component”, and the second side of the membrane facing the second compartment being “an basolateral side” do not further limit the structure of the model.
In claim 22, the abbreviation “huAEC” is understood to refer to human alveolar epithelial cells.
Claim 32 is a product-by-process claim. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore if the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. In the instant case, the 3D in vitro alveolar airway model of claim 32 is interpreted as comprising:
(i) a culture well with a membrane separating the culture well into a first compartment and a second compartment,
wherein the membrane has a first side and a second side,
the first side of the membrane defining a wall of the first compartment, and the second side of the membrane defining a wall of the second compartment;
(ii) alveolar type I epithelial cells present in the first compartment of the culture well; and
(iii) alveolar macrophage-like cells present in the second compartment of the culture well.
Claim Objections
Claim 15, 18, 20, 22, 62, 63 and 65 are objected to for minor informalities:
In claim 15, the formatting of the numbers appears to be in error. Specifically, “1 x 104” should be 1 x 104; “5 x 105” should be 5 x 105, “1 x 105” should be 1 x 105 and “cells /cm2” should be cells/cm2. For purposes of compact prosecution, the claim will be interpreted as if it used the proper superscript format.
Still further in claim 15, in line 2, it appears the phrase should read “… with between 1 x 104 and 5 x 105 of a combination of alveolar type I…”.
In claim 18, the formatting of the numbers appears to be in error. Specifically, “1.75 x 105” should be 1.75 x 105; and “cells/cm2” should be cells/cm2.
In claims 20, 62 and 63, “macrophagelike” should read “macrophage-like”.
In claim 22, the first use of the abbreviation “huAEC” should be preceded by the full term (human alveolar epithelial cells).
In claim 22, the first use of the abbreviation “FBS” should be preceded by the full term “fetal bovine serum”.
In claim 65, the phrase “is selected from one or more of…” implies a Markush group. The proper language is to state “is selected from the group consisting of…” to define a closed group.
Correction is required.
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(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 1, 2, 4, 7, 9, 10, 12, 13, 15, 17-20, 22, 24, 25, 29-32, and 61-64 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 claim 1: Claim 1 is drawn to a method for preparing a three-dimensional (3D) in vitro alveolar lung model. The claim describes the structure/make-up of the 3D in vitro alveolar lung model (lines 2-7), but the claim does not set forth any active steps for preparing the 3D in vitro alveolar lung model. As there are no steps in the method, it is unclear what the metes and bounds of the claim are.
For purposes of compact prosecution, in order to compare to prior art, any method which involves providing a 3D in vitro alveolar lung model having the structure/make-up described at claim lines 2-7 will be considered to read on the claimed method.
Claims 2, 4, 7, 9, 10, 25, 29, 32 and 61 depend from claim 1, none recite method of making steps, thus all inherit the deficiency of claim 1 and are rejected on the same basis.
Regarding claim 12: Claim 12 is the first claim to recite an active method step. Claim 12 requires the method to comprise preparing a culture of a) combination of alveolar type I and type II epithelial cells and b) alveolar macrophage-like cells. There is incongruency between this single active step and the preamble of claims 1 and 12, as it is unclear how preparing a culture of a) and b) achieve the effect of preparing a 3D in vitro alveolar lung model having the features recited in lines 2-7 of claim 1. As such, the metes and bounds of claim 12 are unclear. Specifically, it appears additional essential steps required to achieve the effect are omitted.
Regarding claim 13: There is insufficient antecedent basis for the limitation “the air-liquid interface” in line 7 of the claim. An ALI requires presence of culture medium, as of step ii), no culture medium is present in the first culture well, so no ALI exists, and the membrane cannot be introduced “such that the combination … are present… at the air-liquid interface”.
Claims 15, 17-20, 22, 24, 30, and 62-64 depend from claim 13, inherit the deficiency, and so are rejected on the same basis.
Regarding claim 15: The term “preferably” renders the claim indefinite. It is not clear if the limitations following the word “preferably” are part of the claim or not. See MPEP 2173.05(d). Furthermore, the actual phrase following the word preferably, “the first side of the membrane is seeded with 1 x 105 alveolar type I combination of alveolar type I and type II epithelial cells/ cm2” does not make grammatical sense. It thus not clear what cell type or types or amount of cells would be required on the first side of the membrane if the ‘preferred’ embodiment is required.
Regarding claim 18: There is insufficient antecede basis for the limitation “the culture well” in line 1, as there are two culture wells recited in claim 13, it is not clear which one is being referenced. It is further not clear if the step of seeding the second side of the membrane with leukocytes is in addition to step v), or intended as a substitute for step v).
Regarding claim 22: Claim 22 states the first culture medium comprises huAEC and then in parenthesis recites InSCREENeX, which is a company that produces huAEC culture media. It is unclear if the claim is limited to a specific culture media provided by InSCREENeX, or if this is merely an exemplary embodiment. The metes and bounds of the claim are unclear. See MPEP 2173.05(d).
If the claim is intending to cover the culture medium produced by InSCREENeX, then the claim is further unclear because InSCREENeX is a trademark. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a huAEC culture media and, accordingly, the identification/description is indefinite.
Similarly, the requirement of a huAEC basal supplement, followed by “bovine pituitary extract, insulin, gentamic sulfate and amphotericin (GA-1000), retinoic acid, bovine serum albumin-fatty acid free, transferring, triiodo-L-thyronine, epinephrine, recombinant human epidermal growth factor, InSCREENeX” in parenthesis has the same problems as above. It is unclear if the formulation recited in parenthesis is actually required, or merely exemplary, and again the recitation of the trademark is an improper use of the trademark.
For compact prosecution, the broadest reasonable interpretation of claim 22 is that the first culture medium comprises: a huAEC medium (which will be interpreted as any medium appropriate for huAECs), huAEC basal supplements (which will be interpreted as any supplements that can be added for huAEC culture), FBS and an antibiotic/antimitotic agent.
Regarding claim 29: The term “preferably” in line 3 renders the claim indefinite. It is not clear if the claim is to be limited to PMA or not.
Regarding claim 31: Claim 31 depends from cancelled claim 8. Depending from a cancelled claim renders the dependent claim indefinite. Original claim 8 does not recite any steps, much less a step vii), thus it is not immediately clear what claim 31 should depend from. For purposes of compact prosecution, given that claim 13 is the only preceding claim that recites enumerated steps, claim 31 will be interpreted as if it depended from claim 13.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 repeats step vi) of parent claim 13 with no additional information or limitations, and thus does not further limit parent claim 20.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 7, 10, 12, 25 and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huh et al (US 2018/0216058).
Huh et al disclose biomimetic lung models. In general, the lung model comprises
a base [sic: body],
a membrane, and
a layer of cells (See ¶0005 & 0044).
The base can include a first and second microchannel (See ¶0005 & 0045). The membrane is disposed between the first and second microchannels, such that the first and second microchannels are in fluid communication through the membrane. The membrane has a first side and a second side, with the first side facing the first microchannel, and the second side facing the second microchannel (See ¶0005). The membrane is porous (See ¶0005 & 0048). The layer of cells is present on the first side of the membrane (See ¶0005). The layer of cells can be a combination of alveolar [epithelial] Type I and Type II cells. The cells can be human (See ¶0049). A gel layer can further be present on the second side of the membrane. Additional cell types can be present within the gel layer (See ¶0008). Macrophages can be present within the gel layer on the second side of the membrane (See ¶0051).
The biomimetic lung model described above reads on the three-dimensional in vitro alveolar lung model of the claims as follows: The base (i.e. body) reads on a culture well.
The membrane reads on a membrane configured to separate the culture well into a first compartment and a second compartment. Specifically, the first microchannels read on a first compartment, and the second microchannels read on a second compartment. The membrane has a first side and a second side, wherein each side serves as a wall of the first and second compartments, respectively.
The human alveolar Type I and Type II cells present on the first side of the membrane (in the first microchannel) reads on alveolar type I epithelial cells provided in the first compartment.
The macrophage-containing gel present on the second side of the membrane read on alveolar macrophage-like cells provided in the second compartment. It is noted that any macrophage will read on alveolar macrophage-like cells, given that the “like” permits for a wide breath. However, Huh et al does specifically teach the macrophages can be airway macrophages (See ¶0007).
Regarding claim 1: For the reasons set forth under 35 USC 112(b), claim 1 is being interpreted as only requiring providing a 3D in vitro alveolar lung model as described in claim 1. Huh et al produces the biomimetic lung model described above, and thus anticipates the providing active step of claim 1.
Regarding claim 2: Huh et al teaches the alveolar epithelial cells and the macrophages present in the biomimetic lung can each be immortalized cells (See ¶0050 and 0066).
Regarding claim 7: The first microchannel can be designated an apical compartment, and the second compartment can be designated a basolateral compartment, wherein the first side of the membrane reads on an apical side and the second side reads on a basolateral side.
Regarding claim 10: Huh et al teach the cell layer provided on the first side of the membrane (in the first microchannels/first compartment) can comprise alveolar type I and type II epithelial cells.
Regarding claim 12: Formation of the biomimetic lung model comprising alveolar type I and type II cells, and macrophages reads on preparing a co-culture of all three cell types.
Regarding claim 25: The membrane is porous.
Regarding claim 32: For the reason set forth above, the biomimetic lung model anticipates the three-dimensional in vitro alveolar lung model having the features required by claim 32.
Additional Prior Art References
The following references are considered pertinent to the application, but are not relied upon for rejections at this time.
Sarfraz et al (Mol Pharm, 2016) (cited on IDS of 11/9/2022): Sarfraz et al investigate the role of secondary cytotoxic effects of nanoparticles in a macrophage-lung cancer co-culture model after nanoparticle treatment in presence and absence of anti-inflammatory drugs (See abstract). Sarfraz et al create an in vitro co-culture model comprising MH-S cells (mouse alveolar macrophages) and A549 (adenocarcinoma human alveolar basal epithelial cells, which serve to model alveolar epithelial type II cells). As illustrated in the figure embedded into the abstract, the in vitro co-culture model comprises a transwell plate comprising a porous membrane insert. The MH-S macrophages are seeded on the upper side of the transwell membrane (i.e. in an upper compartment), the A549 cells are seeded in the lower compartment (See “Coculture Experiments” at Pg 3272, col. 1-2).
This co-culture set up is similar to the in vitro co-culture model of the instant claims in that the transwell culture well reads on a culture well provided with a membrane configured to separate the culture well into a first compartment (the upper compartment) and a second compartment (the lower compartment), wherein the membrane has a first side configured to form a wall of the first compartment and a second side configured to form a wall of the second compartment. The MH-S macrophages read on alveolar macrophage-like cells. The MH-S are provided in the second compartment (lower compartment).
The co-culture differs from the in vitro co-culture model of the instant claims in that the A549 are not alveolar type I epithelial cells. A549 cells are adenocarcinoma human alveolar basal epithelial cells that model alveolar epithelial type II cells. Furthermore, it would not have been prima facie obvious to have substituted alveolar type I epithelial cells for the A549 cells, nor to have added additional alveolar type I epithelial cells in combination with the A549 cells. Sarfraz et al specifically chose A549 cells as a lung cancer cell type. Sarfraz et al was delivering anti-cancer drugs to the co-culture, and was measuring the viability of the A549 cells as metric. Thus, A549 cells were required for the method of Sarfraz et al. Substitution of A549 cells with different cell type would have rendered the model unsuitable for the intended use. Inclusion of additional alveolar type I epithelial cells would have diluted the concentration of A549 cells (which would negatively affect the study conditions of Sarfraz et al) without providing any clear benefit to the co-culture model.
Artzy-Schnirman et al (Adv Biosys, 2019) (cited on IDS of 11/9/2022): Artzy-Schnirman et al disclose two ‘anatomically inspired’ microfluidic devices to mimic native acinar airways. The designs are shown in Fig. 1(a) and 1(b). Generally, both designs comprise upper and lower compartments separated by a PET membrane (See Fig. 1(c)). Artzy-Schnirman et al seed hALEVi in the channels of the upper compartment to form a monolayer on the PET membrane (See Pg 2, col. 2-Pg 3, col. 1). Artzy-Schnirman et al then seed alveolar macrophage-like cells (differentiated from THP-1 monocytes) on top of the monolayer of hALEVi cells (See Pg 4, col. 1).
The cell-seeded microfluidic device is similar to the in vitro co-culture model of the instant claims in that the microfluidic device per se reads on a culture well provided with a membrane configured to separate the culture well into a first compartment (the upper compartment) and a second compartment (the lower compartment), wherein the membrane has a first side configured to form a wall of the first compartment and a second side configured to form a wall of the second compartment. The hAELVi cells read on alveolar type I epithelial cells. The hAELVi cells are present in the first compartment. The macrophage-like cells differentiated from THP-1 cells read on alveolar macrophage-like cells.
The cell-seeded microfluidic device differs from the in vitro co-culture model of the instant claims in that the macrophage-like cells differentiated from the THP-1 cells are present in the same compartment as (in fact, on top of) the hALEVi cells. The claim requires the macrophage-like cells to be provided in the second compartment (on the opposite side of the membrane). There is no reason to modify the microfluidic device of Artzy-Schnirman et al to move the macrophage-like cells to the lower compartment.
Quinn et al (US Patent 5750329): Quinn et al disclose an artificial lung organ culture system comprising an upper chamber comprising an epithelial layer, a lower chamber comprising an endothelial layer, and an artificial microporous membrane disposed therebetween (See col. 5, ln 54- col. 6, ln 6). The epithelial layer comprises epithelial cells, and the epithelial cells can be alveolar epithelial cells (See col. 6, ln 40-57). Quinn et al teaches that alveolar macrophages can further be provided in the upper chamber with the alveolar epithelial cell layer. Quinn et al note providing the alveolar macrophages with the alveolar epithelial cells is intentional in order to more closely mimic the in vivo environment within the lung (See col. 9, ln 34-57).
The artificial lung organ culture system of Quinn et al is similar to the in vitro co-culture model of the instant claims in that it includes a culture well provided with a membrane configured to separate the culture well into a first compartment (the upper compartment) and a second compartment (the lower compartment), wherein the membrane has a first side configured to form a wall of the first compartment and a second side configured to form a wall of the second compartment.
However, the model of Quinn et al differs from the instant claims in that they do not specify the alveolar epithelial cells are type I alveolar epithelial cells, and also that when macrophages are included, they are to be provided in the upper (‘first’) epithelial chamber, as opposed to in the lower (‘second’) endothelial chamber on the opposite side of the membrane.
Conclusion
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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