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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 8, 2026 has been entered.
Claim Status
Claims 1, 8-9, 12, 18 and 21 are currently pending in this application.
Election/Restriction
Applicant’s election without traverse of Group I, claims 1-5, 9, and 12-16, in the reply filed on Aug. 7, 2024 is acknowledged. Claim 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Claims 1, 9, 12, 18 and 21 have been considered on the merits and all arguments have been fully considered.
Benefit of Priority Claim
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. As all claims lack written description and enablement as set forth below, all claims lack adequate support and enablement in the manner provided by 35 U.S.C. 112(a) in the priority document CN201811326908.6 filed 11/08/2018 and, thus, the earliest effective filing date of the instant claims is 8/27/2019.
Claim Objections
Claims 1 and 18 inconsistently use italics for the term “ECM1 gene” alternating between “ECM1” and “ECM1.”
Claim 1 is objected to because where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation and, if necessary, plural indentations to further segregate subcombinations or related steps. See 37 CFR 1.75(i); MPEP §608.01(m). Claim 1 recites steps (a)-(c) and sub-steps (b1)-(b4) of step (b) but there appear to be additional elements and sub-steps, such as “(b5)” mating a ECM1 flox/flox mouse with a tool mouse.
Claim 1 is objected to for being unnecessarily verbose and unnecessarily redundant regarding the “non-human mammal” mammal being limited to a mouse or rat (or merely a mouse), which also creates confusion as to which such non-human mammal limitations apply to all the different intermediate non-human mammals recited in the method steps in preparing the final animal model, including in claim 21.
Claim Interpretation
In claim 1 step (a), the ECM1 gene (or inactivated ECM1 gene) is interpreted as meaning only the ECM1 gene in its endogenous position in the genome and not any additional (exogenous) ECM1 transgene at another location, such as in the nuclear/mitochondrial genome, episome or virus.
In claim 1, the term “liver-specific” is interpreted as meaning “liver-limited” as ordinarily used in this art, meaning the gene inactivation occurs in a subset of liver cells or all liver cells but not in any non-liver cells (i.e., not outside liver tissue). This is inapposite of “systemic” gene inactivation as used in the instant application and contrary to the instant application describing at pg. 4 (lines 91-4) that a neuron specific enolase-Cre can be used to make a “liver-specific” knockout mouse. Similarly in claim 21, the term “hepatocyte-specific” is interpreted as meaning “hepatocyte-limited,” which means the ECM1 gene inactivation occurs only in hepatocytes but not necessarily in all hepatocytes, as commonly understood in the art (i.e., not in any non-hepatocyte cell).
In claim 18, the term “inactivated ECM1 gene” encompasses insertions of a selection marker into a non-coding region (e.g., intron) or 3’ coding region, including wherein there is a deletion of ECM1 gene sequence, such as a 3’ coding region. Thus, in claim 1, the term “inactivated ECM1 gene” encompasses modified or edited ECM1 genes lacking 3’ coding regions, which under a broadest reasonable interpretation encompasses the entire sequence 3’ to the endogenous start codon. Note, under a broadest reasonable interpretation, an inactivated ECM1 gene as used in claim 1 only includes floxed ECM1 genes that are “inactive” (i.e., nonfunctional) and, thus, floxed ECM1 genes that are still active are excluded by definition from the term “inactivated” ECM1 gene.
Claim Rejections - 35 USC § 112(a), Written Description
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 1, 9, 12, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
When claim 1 is analyzed in light of the specification, the instant invention is directed to a method of making a liver-specific ECM1 knockout mouse or rat animal model of spontaneous, early liver fibrosis, wherein the method comprises (a) providing a cell of a mouse or rat, inactivating the ECM1 gene in the cell to obtain a mouse or rat cell with inactivated ECM1 gene; and (b) preparing the mouse or rat model using this cell made in step (a) by first preparing and mating chimeric mice or rats to obtain a mouse homozygous for a liver-specific ECM1 inactivated allele of step (a) as recited in sub-steps (b1)-(b4). The dependent claims of claim 1, claims 9, 12 and 20 are also directed to a mouse or rat model of non-human liver fibrosis made by a method according to claim 1 or use thereof.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”.
In the instant case, the claimed methods state a mouse or rat model of non-human mammal liver fibrosis can be made from a mouse or rat cell with an inactivated ECM1 gene by a method comprising (b4) obtaining a homozygous mouse model with liver-specific ECM1 gene inactivation by mating an ECM1 flox/flox mouse with a tool mouse Alb-Cre to obtain a liver-specific ECM1 knockout mouse. The breadth of the “non-human mammal” which is a mouse or rat in the claims encompasses any species of rat or mouse except in step (b4) which requires the “non-human mammal” be a mouse species and the resulting “non-human animal model” be a mouse.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any clear description of a representative number species for this genus by instead describing a single species, a mouse model of uninduced, spontaneous, early liver fibrosis (ECM1-KO) (Examples 1-2). Although another species is described that instead has a hepatocyte-specific gene inactivation (“Alb-cre/ECM1Flox/flox mouse”) via Cre expression from an albumin promoter, no phenotype for early or “non-inducible” spontaneous liver fibrosis was empirical demonstrated for this model (Example 4; FIG. 14). Thus, obtaining an early and/or uninduced spontaneous liver fibrosis model is only prophetically predicted by the method described for performance on inbreed laboratory mouse strains, and the instant application is silent as to how to generate a rat model from a mouse, i.e., via obtaining an inactivated-ECM1 homozygous flox/flox mouse and mating with an Alb-Cre mouse line to obtain a liver-specific ECM1 knockout mouse as required in claim 1(b4).
The instant application provides no description of mating a rat with an Alb-Cre mouse or producing a rat(s) from mating and breeding (i.e., hybridizing) only mice. The instant application provides no example of how to convert or combine any inactivated ECM1 gene lacking flanking flox sites in a mouse with a Alb-Cre mouse to obtain an offspring mouse having ECM1flox/flox. Nowhere does the originally filed application describe how the claimed method might achieve a rat model of early liver fibrosis wherein early is defined as arising within 5-6 weeks in a mouse or how to convert mouse time to equivalent rate developmental time.
There is no description or guidance of how the method achieves the full scope claimed encompassing rat as well as ECM1 genes inactivated without flanking loxP sites (i.e., floxed). Furthermore, there is no description as how to make a liver-specific ECM1-inactivated mouse using an already inactivated ECM1 gene. Instead, the written description represents an invitation to the skilled artisan to experiment figure out whether different inactivation approaches for endogenous ECM1 in mice can be combined with the Alb-Cre mice to create the so-called Alb-cre/ECMflox/flox required by claim 1.
It is unpredictable from claim 1 what/how ECM1 gene inactivation is being achieved when the “homozygous non-human mammal with inactivated ECM1 gene” made in step (b3) appears to create a systemic ECM1 knockout (ECM1-KO) due to the requirement for the ECM1 gene already being “inactivated” in step (a) (e.g., due to 3’ coding deletions made in step (a1)) and the subsequent (b4) step somehow utilizes an Alb-Cre mouse mating to convert this systemic ECM1 knockout into a liver-specific knockout instead. Not a single working embodiment was shown, instead possession of claim 1 is only inferred from evidence from changing activate ECM1flox alleles into inactivated ECM1 genes via Cre, which can be expressed in a liver limited fashion.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any clear description of a representative number species for this genus by instead describing a single prophetic species of mouse, Alb-cre/ECM1Flox/flox, where no liver fibrosis was empirical demonstrated, and especially not non-induced/spontaneous, early liver fibrosis phenotype as required by claim 1 (Example 4; FIG. 14). Thus, the invention of the claims is only prophetically described without evidence of achieving the requisite liver fibrosis conditions. Instead, the only supporting evidence presented is from a different mouse made by a different method than claim 1, systemic ECM1 knockout mice (ECM1-KO) (Examples 1-2).
It is unpredictable that mouse or rat models having both spontaneous and early liver fibrosis genus can be made by the method of claim 1 apparently limited to wherein the ECM1 inactivation phenotype is Abl promoter restricted via transgenic Cre expression. Not a single working embodiment was shown, instead possession of claim 1 is only inferred from evidence from the systemic knockout of ECM1, which presents ECM1 inactivation not only in cells expressing from the Abl promoter, but all cells of the mouse, including all liver cells, not just Abl promoter expressing liver cells (Examples 1-2). Without further evidence, this very different context is not considered representative for the Abl promoter restricted situation. Nothing in the dependent claims (e.g. 9, 18 or 21) fully remedies these deficiencies.
In conclusion, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the scope of rat and mice models encompassed by claim 1.
35 USC § 112(a) – Enablement
Claims 1, 9, 12, 18, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because claim is not enabled to produce a mouse or rat animal model homozygous for liver-specific ECM1 gene inactivation using a method starting with an already inactivated ECM1 gene in a cell as recited in claim 1 step (b), (b1)-(b4).
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue or unreasonable experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” or unreasonable include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The claims are directed to a method of producing a mouse or rat model of non-inducible, spontaneous, early liver fibrosis, which is currently limited to homozygous liver-specific ECM1 gene activation obtained via specifically recited steps and limitations (b1)-(b4).
Mouse or rat with heterozygous or homozygous ECM1 gene “inactivation” made into a mouse or rat with “liver-specific” ECM1 gene inactivation via crossing with a liver-specific Alb-Cre mouse
Firstly, a rat or rat animal model simply cannot be generated from mice, or a process comprising mating mice as recited in step (b4). Similarly, a mouse or mouse animal model cannot be generated using the non-human mammal of any of steps (b1)-(b3) that is a rat. Furthermore, a liver-specific gene inactivation cannot be generated using an already inactivated gene that is unconditionally inactive. For example, an ECM1Flox/flox mouse would not be generated from an “inactivated” ECM1 gene because the presence of the Flox sites does not serve to inactivate the ECM1 gene but rather prepare for a future inactivating step after exposure to Cre expression.
Claim 1 is directed to a method of making a mouse or rat having a liver-specific ECM1 gene inactivation comprising the steps of (b1) obtaining a mouse or rat cell with inactivated ECM1 gene and making a chimeric mouse or rat comprising said cell, (b2) mating the chimeric mouse or rat to a wild-type mouse or rat and screening their offspring to obtain a mouse or rat heterozygous for the inactivated ECM1 allele, (b3) mating heterozygous mice or rats to obtain a mouse strain homozygous for the inactivated ECM1, and (b4) hybridizing the homozygous mice with a liver-specific knockout mouse by mating an ECM1 flox/flox mouse with an Alb-Cre liver specific knockout mouse to obtain a mouse model having liver-specific ECM1 gene inactivation (homozygous).
In other words, the end result of the claimed method is liver-specific ECM1 gene inactivation mouse somehow obtained from any “inactivated” ECM1 gene in a mouse or rat cell and wherein the method comprises mating/breeding a chimeric mouse or rat with a wild-type mouse or rat as well as creating a mouse or rat homozygous for the inactivated ECM1 gene prior to hybridizing with a liver-specific knockout mouse. It is not clear from the claim language how the ECM1 flox/flox mouse relates to the cell, chimeric mouse or rat, and the homozygous mouse or rat each with the already inactivated ECM1 gene. Similarly, claim 12 is directed to a subset of models made by the claimed method wherein the mouse or rat can survive for at least 8 weeks despite having spontaneous, early liver fibrosis within 5-6 weeks referenced to generic/typical mouse life.
Breadth of the claims: inactivated ECM1 gene prior to step (b)
Claim 1 is broadly directed to a method of making a mouse or rat having spontaneous, early liver fibrosis wherein the intermediate steps comprise any ECM1 gene inactivation and necessarily comprises a mouse (but not a rat) as well as mating/breeding mice or rats of any mice or rat species with each other to obtain offspring (i.e., heterozygotes, homozygotes, and hybrids).
Thus, claims 1, 9, 12, 18, and 21 encompasses methods of making a liver (such as a hepatocyte-specific knockout) using any ECM1 gene inactivation to somehow obtain a ECM1 flox/flox mouse. Further, claims 1, 9, 12, and 18 encompasses methods of making a rat model using a mouse intermediate. Additionally, claims 1, 9, 12, 18, and 21 encompasses methods of making mouse models using any combination of mice of the same species.
The state of the art:
The prior art is silent as to wherein a single mouse or rat animal model having liver-specific homozygous ECM1 gene inactivation (or further hepatocyte-specific) can be created from a mouse or rat cell with any inactivated ECM1 gene. The prior art is also silent as to wherein a single mouse or rat animal model having liver-specific homozygous ECM1 gene inactivation can be used to model spontaneous/uninduced early liver fibrosis. The prior art is also silent as to how to make a rat from a genetically modified mouse.
As the prior art does not teach or predict such a situation, these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden being on such an artisan.
The amount of direction and guidance and working examples provided by Applicant:
As noted in the previous office action, the working example and guidance are silent as to how make an animal model with liver-specific and/or hepatocyte-specific gene inactivation from a cell wherein the gene is already inactivated generally. The working examples and guidance also fail to show how to make a rat using matings of mice intermediates, such as with a Abl-Cre mouse.
Vitally, the instant application fails to provide a liver-specific working example, instead describing only a pan-tissue ECM1 knockout mouse having spontaneous/uninduced early fibrosis by week 5-6. While the instant application at Example 4 and FIG. 14 describes a liver-specific working example, limited to single species of hepatocyte subtype specific (parenchymatous) (homozygous ECM1-KO mice (Alb-cre/ECM1Flox/flox) aligning with claim 21), there is no evidence provided that these mice can model spontaneous or early liver fibrosis, or any other type of non-human liver fibrosis. However in light of teaching a method of making a mouse model of uninduced, spontaneous, early liver fibrosis using a liver-wide global knockout (ECM1-KO) (Examples 1-2), it is not unreasonable to conclude at least some liver-specific homozygous ECM1-KO mice would develop uninduced, spontaneous, early liver fibrosis phenotypes even if every parenchymatous-specific version does not. However, this is still unpredictable.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to make a liver-specific or hepatocyte-specific ECM1 inactivation mouse from a cell already having an ECM1 inactivated status, and may never be achievable. The examples and guidance provided, while extrapolatable to other liver-specific promoters and floxed “active” ECM1 constructs, do not provide sufficient guidance without a working example of this extraordinary assertion. Thus, undue and unreasonable experimentation is required to achieve claim 1 as currently drafted.
Moreover, extensive experimentation would be required to determine how to make a mouse or rat homozygous for ECM1 inactivation at least in or limited to hepatocytes to reliably model spontaneous/uninduced early liver fibrosis by mouse age week 5-6. The example provided with systemic ECM1 inactivation is not extrapolatable/predictable to any liver-specific promoter limiting ECM1 inactivation in mice generally (e.g., Cre expression limited to only Kupffer, hepatic stellate and/or sinusoidal endothelial cells via e.g., via a Clec4f, Esm1, Des, Lrat, and/or Gfap promoter). Thus, undue and unreasonable experimentation is required across the entire scope of the claims, which may never be successfully achieved for producing a rat model or any liver-specific model.
In summary, claims 1, 9, 12, 18, and 21 are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement, to a person skilled in the art to which it pertains or with which it is most nearly connected to, to make/use the claimed mouse or rat model. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the strict requirement for liver-specific inactivation and uninduced spontaneous liver fibrosis by 5-6 weeks mouse age; undue and unreasonable experimentation would have been required for one skilled in the art to perform the claimed methods to produce the recited animal model, which may never be achieved.
Response to arguments
Applicant arguments were not found persuasive as discussed below. In the response filed 6/8/26, applicant argues written description support and enablement (pg. 6-9) based on several points (pg. 7) contrary to or missing from the claim limitations:
claim 1 does not “explicitly specify that the starting cell is suitable for homologous recombination,” as nothing in the claims requires the cell be “suitable” for homologous recombination, such as limited to having any specific feature(s) of a mouse embryonic stem cell;
claim 1 fails to clarify a Cre-loxP system is used in any specific way and nowhere do the claims require gene editing to obtained an ECM1 gene flanked by loxP sites, instead discussing non-liver specific ECM1 gene inactivation prior to step (b4);
Step (b4) fails to clarify that any ECM1flox/flox mouse is obtained in step (b3) or how an already inactivated ECM1 gene is made liver-specific via step (b4) as argued.
In support of the 112(a) rejections above, Applicant’s own arguments admit that the ECM1 is not inactivated but rather “permits” subsequent conditional knockout, which is contradicted by the instant claim language as interpreted herein. Claim 1 fails to clearly describe the process of constructing a floxed ECM1 allele and obtaining a liver specific knockout, instead providing method steps incoherent with each other (see 112(b) rejections). Moreover, as noted above all the empirical data regarding spontaneous early liver fibrosis at 5-6 weeks of age in a mouse is based only a systemic ECM1 knockout as no fibrosis data is provided for the hepatocyte-specific knockout discussed in the response and no such evidence is provided in the prior art.
Claim Rejections - 35 USC § 112(b)
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, 9, 12, 18 and 21 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 pre-AIA the applicant regards as the invention.
Claim 1 is indefinite for undue unwieldiness regarding the “non-human mammal” animal being either a mouse, mouse or rat, or some other mammal entirely, failing to conform with current U.S. practice to ensure the invention as claimed is comprehensible enabling proper examination and avoiding needless ambiguity. Claims 9, 12, and 18 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites, preceding step (b), a step (a) comprising an “inactivated” ECM1 gene; however if the ECM1 gene is “inactivated,” then the step (b) sub-step (b4) of mating an ECM1 flox/flox mouse with an Alb-Cre mouse to obtain a “liver-specific” ECM1 inactivated mouse is incoherent as to how an ECM1 gene inactivated in an unlimited manner (the mammals homozygous for inactivated ECM1 gene produced in step (b3)) is somehow converted/restricted to an ECM1 gene only inactivated in a “liver-specific” limited way. As noted in the previous office action, it is incoherent how a liver-specific ECM1 inactivation mouse or rat is derived from a mouse or rat cell already having ECM1 “inactivated” unlimited by any liver specific feature. Further, it is incoherent how a mouse or rat is made from intermediate ones having unlimited generic ECM1 inactivation by method comprising a step of hybridization with a liver-specific knockout mouse and/or mating an inactivated ECM1 flox/flox mouse with an Alb-Cre mouse as recited in step (b4). Either the ECM1 gene is not inactivated prior to step (b4) or the resulting model cannot be liver-specific based on the method steps as recited. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1. Similarly in claim 18, it is not clear how an ECM1flox/flox or “Alb-cre/ECM1flox/flox“ mouse in step (b4) relates to ECM1 inactivation in a liver specific manner when the ECM1 gene is already inactivated, such as due to deleting or editing to obtain an “inactivated” ECM1 gene.
Step (b1)-(b2) recite a “chimeric” non-human mammal, which is ambiguous as to whether referring to the mammal having cells of two or more different animal species (e.g., a xenotransplantation) or having cells all of the same species but genotypically chimeric at the endogenous ECM1 locus (i.e., comprising a combination cells either having an inactivated ECM1 allele(s) or only having an active (e.g., wild-type) ECM1 gene. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
In claim 1, step (b4) comprises mating “a ECM1 flox/flox mouse” with an Alb-Cre mouse of the same species. As the choice of preposition preceding ECM1 flox/flox mouse (‘a’) indicates no antecedent for this term previously in the claim, it is ambiguous as to any relationship between introducing “a ECM1 flox/flox mouse” and the homozygous non-human mammal with inactivated ECM1 gene obtain in step (b3). Must the homozygous non-human mammal with inactivated ECM1 gene be limited to an a ECM1 flox/flox mouse? Thus, a person of ordinary skill in the art would not understand the metes and bounds of any limitation(s) imposed by this mating as presently worded. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
In step (b4), claim 1 also recites the term a “liver-specific knockout non-human mammal of the same species,” which is incoherent, ambiguous and unclear as to what gene/function is knocked-out as it is being mated with mammal(s) comprising generically inactivated ECM1 genes. Further, step (b4) additional requires a mating of an ECM1 flox/flox mouse with an Alb-Cre tool mouse to obtain a liver-specific knockout mouse. Thus, it is incoherent, ambiguous and unclear as to whether the liver-specific knockout non-human mammal mouse is referring to the “tool mouse Alb-Cre” in this subsequent phrase or an some undefined liver-specific knockout mouse as an Alb-Cre mouse does not fall within the definition of a “liver-specific knockout” mouse. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites the term “tool mouse Alb-Cre,” which is neither defined in the claim nor the instant specification. Thus, a person of ordinary skill in the art would not understand the metes and bounds of any limitation(s) imposed by the term “tool.” For purposes of examination herein, this term was considered to mean any Alb-Cre mouse with the term “tool” providing no limitation. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites the parenthetical phrase “referred to as an Alb-cre/ECM1flox/flox mouse,” which is indefinite because it is not clear if the phrase is a claim limitation, an optional feature or introducing a nomenclature never used again in the claims. Claim 1 also recites the parenthetical phrase “;i.e., a liver-specific ECM1 inactivated mouse,” which is indefinite because it is not clear if the phrase is a claim limitation, an optional feature or extraneous commentary. Also, there appears to be a typographical error in the lack of space between the semicolon and ‘i.’ If the “liver-specific ECM1 knockout mouse” in step (b4) is intended to be “the liver-specific ECM1 inactivated mouse” having antecedent basis in the claim before this phrase, then the language should clearly state such. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites the term “normal wild-type non-human mammal,” which is incoherent, ambiguous and unclear as to what limitation the term “normal” places on this mammal. This could serve to differentiate between ‘normal’ and ‘abnormal’ wild-type mammals, but then the meaning of the term “wild-type” comes into question. Alternatively, normal could merely be synonymous and redundant with wild-type, among even other interpretations. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
Claim 1 recites the relative term “early” with regard to a rat model of liver fibrosis. While the claim 1 provides a definition for “early” with regard to a mouse as appearing within 5-6 weeks, neither the prior art nor the specification provides a definition or standard for measuring a requisite degree of “early” liver fibrosis for a rat, and thus, a person of ordinary skill in the art would not understand the metes and bounds of “early” in the claim regarding a rat model. Claims 9, 12, 18 and 21 are included in this rejection for depending from indefinite claim 1.
Response to arguments
In the response filed 6/8/26, applicant argues the claims are definite due to the claim amendments that explicitly describes the starting cell as an ECM1-floxed cell (pg. 9-10); however to the contrary, the claims are silent as to an ECM1-floxed cell prior to step (b4).
Claim Rejections - 35 USC § 112(d)
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claim 21 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 21 attempts to narrow the animal model to ones which are hepatocyte-specific. However the instant application describes Abl-Cre as providing hepatic parenchymatous cell specific expression (pg. 21, lines 14-22; Example 4, FIG. 14) and thus any liver specific ECM1 inactivated mouse made by a method comprising crossing an ECM1 flox/flox mouse with an Alb-Cre mouse to use a mouse with an “Alb-cre/ECM1flox/flox“ genotype to make the model will inherently be hepatocyte-specific due to the Alb promoter. Thus without clarification or appropriate amendment, claim 21 prima facie fails to further limit the subject matter of claim 1. To the extent applicant argues to the contrary, then please consider the relevant 112(b) rejection above regarding the incoherence as to how an already inactivated ECM1 is converted to a tissue/cell-type limited inactivation by a step (b4) of mating ECM1 flox/flox mice with Alb-Cre mice.
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.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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