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 with traverse of Group II, claims 11-18 in the reply filed on 07/24/2025 is acknowledged. The traversal is on the ground(s) that Groups I, II and IV share an inventive concept. Applicant argues that Groups I,II and IV share the same concept that zebrafish xenografts can report on the innate immune component of the TME. Applicant argues that Invention I enables the discovery of genes and Invention II builds on that to screen for compounds that can reprogram the TME and Invention IV translates findings into the clinic. Applicant also argues that the three Groups share features such as the same zebrafish xenograft system , use imaging and quantification of tumor burden, transgenic reporters and engraftment rate. These arguments are not found persuasive because the inventions are separate features in a field of endeavor. Because one can build upon the other does not render them patentably indistinct. Sharing common concepts, tools or reagents does not render the invention to be indistinct one from the other. The requirement is maintained for reasons of record.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-10 and 19-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07/24/2025.
Claim Objections
Claims 11 is objected to because of the following informalities: Claim 11 should begin “An in vivo method”. Step a) should read “generating a zebrafish”. The preamble refers to “xenografts” (plural” while the method steps generate a singular xenograft. Reference to “zebrafish xenografts” in the preamble infers grate cells are zebrafish cells. Given the body of the claims, it is clear the host is a zebrafish. The preamble would be more clear if it stated “a zebrafish xenograft model”. Appropriate 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 (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 11,12,14-16 and 18 remain 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.
The rejection of claim 11 based on the use of vague language or omission of steps is withdrawn in light of the clarifying amendment of step a. However, it necessitate the objection to language in the preamble (above).
The rejection relating to step b is withdrawn.
Step c remains unclear. While Applicant has added a basis of comparison to determ the claimed reduction, it refers to untreated controls. THe claim does not refer to a treated sample. The claim would be more clear if step b referred to a treatment such as “treating the zebrafish xenograft model by injecting…” so that there is a clear treatment group to which ‘untreated controls” are compared. as the term “reduction” is relative and the claim does not set forth what the reduction is relative to.
Step d remains wholly unclear with regard how transgenic or immunocompromised fish are used to validate a compound and how the microenvironment is related to the validation. The newly added term “analyzing” is vague. It cannot be determined what steps are taken in validating the immunomodulator and what outcome from the analysis indicates a result. It is not clear if the transgenic hosts and the immunocompromised zebrafish are the xenografts generated in step a or if they are separate. Step d has been amended to recite “analyzing…zebrafish xenografts” rendering it unlcear if the hosts/zebrafish of d are the xenografts of a)
Claims 13-16 and 18 are also unclear as they depend from claim 11 and fail to add clarity.
Claim 16 remains unclear. Parent claim 11 now recites hat the innate immunomodulators are injected and claim 16 recites that they can be added 24 hours post injection. It is not clear how they can be added post injection if they are the injection. It appears perhaps there is a lack of clear antecedent basis because claim 11 has two different injections-the grafting of cells and the introduction of a potential immunomodulator.
Claim 18 remains unclear as to how an immunocompromised fish can be a chemical or a morpholino. This aspect of the rejection was not addressed by any amendment to the claim and Applicant failed to remark on this this rejection.
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 11,12,14-16 and 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
A method for identifying innate immunomodulators to boost tumor clearance using a zebrafish xenograft model comprising the steps of:
a) generating zebrafish xenograft model by injecting progressor tumor cells into a zebrafish embryo or larva;
b) treating the model by adding at least one test compound to the water housing the zebrafish model;
c) quantifying the engraftment rate of the treated model and selecting compounds that lead to at least a 20% reduction of engraftment in treated zebrafish compared to an untreated control; and
d) validating the selected compounds as innate immunomodulators to boost tumor clearance when,
i) the compound leads to a higher proportion of TNFa+/mpeg+ macrophages in the tumor microenvironment of the zebrafish model comprising progressor tumor cells than in the same model that is not treated with the compound, and/or
ii) the compound does not lead to a reduction in progressor cell engraftment when the model is immunocompromised as a result of a lack of neutrophils and/or macrophages;
does not reasonably provide enablement for quantifying and selecting a compound without appropriate comparison or validating as so generally recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "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 experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). 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 weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to screening agents for innate immunomodulators that boost tumor clearance. While tumor xenograft models in zebrafish were known in the art at the time of filing, these methods did not selectively utilize “progressor” cells with high levels of engraftment or validate antitumor agents using zebrafish expressing transgenic marker genes that enabled the artisan to determine that the innate immune cell population in the tumor microenvironment (TME) was affected by the agent.
The claims remain broad at step d. Step c now recites how to determine reduced engraftment, i.e. compare treated engraftment numbers to untreated controls wherein the engrafted cell number is reduced in the treated vs untreated control fish (see Specification at para 74). Step d appears to be a separate validation step where the mechanism of action of the compound is tested to determine if the compound reduces engraftment through immune modulation. As claimed, this step requires only “analyzing”. There is no comparison or clear readout that is used to make a determination of “validity”.
Turning to the Specification, the first validation method uses transgenic fish that have visible markers expressed under control of the TNFa gene and the mpeg gene promoters. It is presumed this is the “transgenic host” recited in step d. TNFa and mpeg are markers of the M1N1 type macrophages and neutrophils that are “COLD” and suppress tumor engraftment via tumor cell clearance. Progressor tumor cells are able to engraft in these transgenic fish by causing the M1N1 type cells to the convert to the M2N2 state, that is referred to as “HOT” and allows tumor cell engraftment. For the claimed model, transplanted with progressor cells, the presence of a compound that is an innate immunomodulator would lead to an increase in TNF1a/mpeg1 directed transgene expression if the compound modulates the polarity of M2N2 macrophages and neutrophils in the progressor cell TME to M1N1 polarity and a tumor suppressive microenvironment amongst the xenografted progressive cells (that usually create an M2N2 TME). Thus, once a compound is selected in step c, it’s mechanism of action is validated by showing it alters the TME and switches the M2N2 environment to an M1N1 TME.
Step d also encompasses a second embodiment where immunocompromised fish are used in compound validation (separate from the transgenic host). The Specification teaches using mutant fish (runx1 and/or panther mutants) that are deficient for neutrophils and/or macrophages, respectively; and shows that progressor cells form more engrafted tumors in the mutants than they do in wildtype fish. These mutant fish are not able to clear the progressor tumor cells as a result of lacking immune cells. If a compound acts by reversing neutrophil and/or macrophage polarity in an M2N2 TME, progressor cells will see an increased engraftment in the presence of the compound (few immune cells in the TME to clear the progressor cells-the compound does nothing) while progressor cells will see no change in levels of engraftment because the compound has no immune cells to reverse to an M1N1 “COLD” state (see para 114). Similarly, when the compound is added to a model harboring progressor cells, no change in engraftment will be observed because there are no macrophages or neutrophils to switch polarity to a tumor-suppressive M1N1 state.
The claims are not enabled for their full breadth due to the lack of method steps or details that limit the claims in light of the teachings in the specification. The claims are vague and indefinite for reasons set forth above. Adding details of the method steps to the claims in accordance with the guidance in the specification should address this rejection.
Applicant remarks that the pending claims are directed to a method for identifying innate immunomodulators using a zebrafish xenograft platform wherein the innate immunomodulators are selected based on their ability to induce tumor clearance through modulation of the TME and subsequently validated for translational relevance. This fails to address the rejection as set forth above. The main issue is with step d and what is actually being analyzed and how that translates into validation. The step is very broad with how transgenic hosts and immunocompromised hosts are used.
Comment
Applicant provides lengthy arguments regarding the citation of Haney and Xiao as prior art made of record but not relied upon. This is merely a citation of relevant art and is not a rejection. These arguments are not addressed as there is not relevant rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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