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 .
Status of the Claims
Claims 1-13 are pending and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/EP2021/085982, filed on December 15, 2021. The instant application claims foreign priority under 35 U.S.C. 119(a)-(d) to European Patent Application EP20215095.9, filed on December 17, 2020. A certified copy of the foreign patent application in the original language has been provided with the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 15, 2023; July 27, 2023; and February 5, 2025 are is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the Fig. 2 drawing captions appear to be in the originally-filed language and do not match the compounds names or concentration indicators in the Example section of the instant specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in Para. [0006] of the specification. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 1-9 and 13 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 clearing of tissue using 2-hydroxy-5-methoxybenzaldehyde (alternatively indicated as “m-Anisaldehyd” in the drawings) at concentrations between 80-100%, does not reasonably provide enablement for the full scope of benzaldehyde anisole ethers as instantly claimed at the full scope of concentrations of benzaldehyde anisole ethers as instantly claimed nor does the specification provide support for subsequent visualization by light microscopy. 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. Applicant’s disclosure does not provide enough information for any person skilled in the art to use any of the instantly claimed embedding mediums at any of the instantly claimed concentrations for clearing tissue for any subsequent visualization by light microscopy.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of benzaldehyde anisole ethers comprising 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde which can be used at many concentrations for use in clearing tissue samples prior to subsequent visualization using light microscopy. As discussed supra, the specification fails to describe the full genus of compounds which can be used for tissue clearing and at which specific concentrations and would require undue experimentation to discover these compounds and concentrations. The specification only discloses and provides guidance for tissue clearing using 2-hydroxy-5-methoxybenzaldehyde at concentrations between 80-100%.
Independent claim 1 and 13, and dependent claim 4 encompass a genus of benzaldehyde anisole ethers comprising 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde for use in clearing tissue samples while the working examples of the specification only discloses a single species, 2-hydroxy-5-methoxybenzaldehyde, of the claimed benzaldehyde anisole ether.
Dependent claims 2 and 3 encompass a genus of concentrations of benzaldehyde anisole ethers for use in clearing tissue.
Dependent claims 5-8 encompass a genus of dehydration steps.
Dependent claim 9 encompasses a genus of light microscopy techniques for visualizing internal tissue structure.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” 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 is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for the full scope of claimed benzaldehyde anisole ethers and claimed concentrations. The absence of working examples directed to several of the claimed benzaldehyde anisole ethers and use at a wide range of concentrations necessitates further experimentation. Additionally, no working examples were provided that utilize 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, or 4-ethoxybenzaldehyde nor were working examples provided that utilize concentrations of 2-hydroxy-5-methoxybenzaldehyde below 80%. Therefore, the specification does not provide sufficient guidance on how to make and use the full scope of the instantly claimed benzaldehyde anisole ethers at the full scope of the instantly claimed concentrations for tissue clearing and subsequent visualization of the internal structure of the tissue via light microscopy.
In regard to claims 1 and 4 encompassing a genus of benzaldehyde anisole ethers comprising 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde; the specification shows a working examples to a single embodiment of 2-hydroxy-5-methoxybenzaldehyde (Examples 1-3).
In regard to dependent claims 2 and 3 encompassing a genus of concentrations at which the benzaldehyde anisole ethers can be used to clear tissue, Applicant discloses a fixed number of concentrations (80-100%) of only 2-hydroxy-5-methoxybenzaldehyde (Example 2).
In regard to dependent claims 5-8 encompassing a genus of dehydration steps; as stated above, the specification shows a working examples to a single embodiment of 2-hydroxy-5-methoxybenzaldehyde (Examples 1-3).
In regard to dependent claim 9, encompassing a genus a genus of light microscopy techniques for visualizing internal tissue structure, Applicant has provided images of tissue which appears clear in comparison to controls but no working examples of visualization of internal tissue structure using light microscopy.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that tissue clearing has highly variable results based on the compound used and that each specific compound or combination of compounds requires optimization in order to generate results that are useful for subsequent visualization of tissue structural elements. Consequently, there is ample reason to conclude that there would be a high degree of unpredictability between embodiments of the instant invention.
Becker et al. (2012, Correction: Chemical clearing and dehydration of GFP expressing mouse brains. PLoS One, 7(8), 10-1371, found in IDS) teaches testing of many different compounds and their effectiveness for use in clearing of GFP positive tissues (Fig. 4). Becker et al. indicates that compounds comprising hydroxyl groups (for example, 2-hydroxy-5-methoxybenzaldehyde) are GFP-incompatible and greatly reduced the ability to visualize GFP positive samples (Pg. 4, left column) thus indicating there is an amount of unpredictability regarding use of various clearing compounds and also that some compounds, while being effective for clearing, may not be effective for specific types of subsequent visualization by light microscopy.
Chiang (US 6,472,216 B1) discloses an aqueous tissue clearing solution comprising dimethyl sulfoxide, diatrizoate acid, ethylenediaminetetraacetic acid, glucamine, β-nicotinamide adenine dinucleotide phosphate, sodium diatrizoate, and derivatives of polyoxyalkalene (Col. 2, lines 2-6)) which can be used without damaging tissue and without dehydration of tissue (Col. 1, lines 48-50). Chiang discloses that prior tissue clearing agents required solvent extraction which can distort tissue morphology (Col. 1, lines 36-38) and are not suitable for all uses.
Imai and Ke (US 9,933,342 B2) discloses a clearing reagent comprising fructose (Abstract) which does not cause swelling or shrinkage of biological material and thus prevents tissue deformation (Col. 7, lines 45-49) which is superior to other known clearing solutions which suffer from technical problems such as reduction of fluorescence due to use of an organic solvent (Col. 2, lines 25-30) or are not able to generate sufficient tissue transparency and also can cause tissue shrinkage (Col. 2, lines 31-32) which would obviously inhibit subsequent visualization of internal tissue structure.
Therefore the teachings of the prior art indicate that clearing of tissue is not one-size-fits-all and that a significant amount of optimization is necessary for each specific tissue clearing compound and also that the specific agent which is chosen for use should be optimized with the requirements of subsequent visualization in mind.
Since the prior art at the effective filing date of the present application did not provide guidance for using benzaldehyde anisole ethers comprising 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde to clear tissue samples for further visualization using light microscopy, it is incumbent upon the instant specification to do so. As detailed above, the physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to tissue clearing, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to use the claimed invention for clearing of tissue. Given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to make and use the invention beyond the scope of the working embodiment of 2-hydroxy-5-methoxybenzaldehyde at concentrations between 80-100%.
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 2-3, 5-6, and 13 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.
Claims 2 and 3 recite the term “optically suitable” in line 3 which is a relative term which renders the claim indefinite. The term “optically suitable” 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. As there is no guidance provided for what constitutes an “optically suitable” inert organic solvent, one having ordinary skill in the art would not be able to easily determine which inert organic solvent could be used in the instantly claimed method.
Claims 2 and 3 recite the limitations “of about 1.3, preferably 1.5” and “of about 2.0, preferably 1.65” respectively in lines 3-4. The use of the term “preferably” renders the scope of the claim unclear as it is not clear which refractive index is intended to be instantly claimed.
Claim 5 recites a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “dehydrating compositions composed of aqueous alcohol, ketone, or ether…”, and the claim also recites “aqueous mixture of aqueous ethanol…” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 5 recites the limitation "the solvent" in line 4. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of a solvent.
Claim 5 recites the limitations “preferably 70% to 98%, more preferably 75% to 98%” in lines 5-6. The use of the term “preferably” render the scope of the claim unclear as it is not clear which concentration is intended to be instantly claimed.
Claim 5 recites the limitation “an aqueous mixture of aqueous ethanol having increasing concentrations of ethanol” which renders the scope of the claim indefinite. This limitation refers to a single aqueous mixture of aqueous ethanol thus it is not clear how a single aqueous mixture would have increasing concentrations of ethanol.
Claim 6 recites the limitation "the gradient" in line 4. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of a gradient.
Claim 6 recites the limitation “small increments” in line 5 which is a relative term which renders the claim indefinite. The term “small increments” 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. As there is no guidance provided as to what constitutes “small increments”, one having ordinary skill in the art would not be able to easily determine what specific increments could be used in the instantly claimed method.
Claim 13 is written as a “method of use” claim but contains no method steps and is therefore indefinite. As claim 13 contains no method steps reciting how the method of use is to be applied, it is not clear how one having ordinary skill in the art would practice the instantly claimed method. See MPEP 2173.05(q).
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 11 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 11, which depends from claim 10, recites wherein the benzaldehyde anisole ether is selected from 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde. However, claim 10 already recites wherein the benzaldehyde anisole ether is selected from 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde. Thus, claim 11 does not further limit claim 10 from which it depends. 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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 13 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because the claim embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. See MPEP §2173.05(p).
In Clinical Products Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966), the district court held the following claim was not a proper process claim under 35 U.S.C. 101: "The use of a sustained release therapeutic agent in the body of ephedrine absorbed upon polystyrene sulfonic acid."
Claim 13 recites a product (“a benzaldehyde anisole ether”) and a method (“for use…as an embedding medium” in the same claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 10-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN 103582475B (Espacenet translation attached, hereafter CN ‘475B).
Claims 10, and claims 11 and 12, which depend from claim 10 recite a kit with the intended use of “preparing biological tissue samples for light microscopy” comprising a solvent having the intended use of “dehydrating the tissue sample” and an embedding medium “for clearing the dehydrated tissue sample by placing the sample in the embedding medium”. The intended use of the kit, dehydrating solvent, and embedding medium as instantly claimed does not appear to impart any structural limitations on the instantly claimed components and is therefore not interpreted to be limiting. Further, claim 10 recites where in the “embedding medium is… 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, and 4-ethoxybenzaldehyde” and is also therefore interpreted as indicating no structural difference between the instantly claimed compounds and the embedding medium.
With regard to claims 10-12, CN ‘475B discloses an oral composition for tooth whitening (Para. [0013]) which can be used in a kit (Para. [0087], line 6) wherein the oral composition comprises ethanol (Para. [0025]) and may comprise a flavoring (Para. [0051], line 5) wherein the flavoring may be anisaldehyde (Para. [0062], line 14).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631