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 CON of PCT/ PCT/CN23/84978 filed on March 30, 2023 which claims priority to foreign application No. PCT/CN22/84562 filed on March 31, 2022, a certified copy of which is found in the parent application.
Claim Objections
Claims 1, 15-16, 25 are objected to because of the following informalities:
Regarding claim 1, claim 1 recites:
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. For clarity, the X limitations should read as:
“X5 is N or CH if X5 is part of a double bond…” without the commas after each “X# is N”.
Further regarding claim 1, claim 1 recites “per se” twice, in regards to R2 and R5 definitions:
“…each of said -C1-8alkyl, C2-8alkenyl, C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl per se or as a moiety in C1-8alkoxy, C2-8alkenoxy, C2-8alkynoxy, cycloalkoxy, aryloxy, heterocyclyloxy, or heteroaryloxy is unsubstituted or substituted with halogen, …” (emphasis added).
The “per se” limitation appears to be extraneous, and the Examiner suggests amending to read as follows for clarity:
“…each of said -C1-8alkyl, C2-8alkenyl, C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, ,
Regarding claim 15, claim 15 recites:
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but the first moiety listed is missing the ** attachment indicator.
Regarding claim 16, claim 16 reads “The compound of claim 1 wherein R4a and R4b are each hydrogen or C1-6 alkyl; or R4a is hydrogen, and R4b is C1-6 alkyl; R4a C1-6alkyl; and R4b is hydrogen” which is awkward and extraneous. For clarity, the claim should read “The compound of claim 1 wherein R4a and R4b are each hydrogen or C1-6 alkyl.”
Regarding claim 25, the list of diseases appears to be missing a conjunction (e.g. “and”, “or”).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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.
Claim 25 is 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 treating a BCL-xL mediated disease wherein the BCL-xL mediated disease is selected from solid tumors, hematological malignancies, virus infection, immune and inflammatory diseases, age-related diseases, and central nervous system-related diseases, does not reasonably provide enablement for preventing or treating solid tumors, hematological malignancies, virus infection, immune and inflammatory diseases, age-related diseases, central nervous system-related diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the nature of the invention,
2- the breadth of the claims,
3- the state of the prior art,
4- the predictability of the art,
5- the amount of direction or guidance provided
6- the presence or absence of working examples,
7- the quantity of experimentation necessary, and
8- the relative skill of those in the art.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Undue experimentation is required by one skilled in the art to determine enablement of the instant disclosure as claimed due to the following:
The nature of the invention (1) and the breadth of the claims (2)
The nature of the invention and breadth of the claim is the treatment or prevention of the diseases specifically listed in claim 25.
The specification defines “disease” as “any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term ‘disorder’ or ‘condition’” (see instant spec. at p. 20 ¶[0080]).
The specification does not define “prevention”, “treatment”, or “subject”.
Furthermore since subjects could include cells and individuals and prevention and treatment could include prophylaxis and not worsening, the broadest reasonable interpretation includes a patient population of anyone.
The state (3) and predictability (4) of the art
MPEP § 2164.05(a) states if a publication demonstrates that those of ordinary skill in the art would not find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing.
Regarding unpredictability in preventing cancer, Meyskens et. al.1 states, “Establishing the benefit of new cancer preventive interventions will take years and possibly decades, depending on the outcome being evaluated. We also propose that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary in order for preventive interventions to become a routine part of cancer management” (see Meyskens at Abstract). Therefore, cancer prevention is not well-established in or predictable in view of the art. It is unclear how the claimed method would achieve prevention in the vast array of cancers listed when such a field is expected to require several more decades of research to bring forth practical predictable applications.
Regarding unpredictability in preventing or treating CNS diseases, Danon et. al.2 teaches challenges in developing treatments for CNS diseases include an incomplete understanding of the biology of multifaceted CNS conditions such as Alzheimer’s disease, the presence of a blood–brain barrier that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models in which to test new drugs (see Danon at Abstract). Danon teaches CNS diseases include a diverse range of conditions such as social and mood disorders (e.g., clinical depression, addiction), neurodegenerative diseases (e.g., Alzheimer’s, Huntington’s, and Parkinson’s diseases), brain cancers (e.g., glioblastoma), neuropathic pain, and stroke (see Danon at p. 1 ¶2). Danon even states "once a lead compound has been developed, the journey is far from over" when reflecting on the challenges CNS drugs face in clinical trials like off-target effects (see Danon at p. 9 ¶4 and p. 10 Boxes 1 and 2).
Regarding unpredictability in treating diseases with BCL-xL inhibitors, Hafezi et. al.3 teaches BCL-xL inhibitors such as ABT-737 and ABT-263 faced clinical development problems for treating non-small cell lung cancer, lymphoid malignancies, and small cell lung cancer such as poor pharmacokinetic and solubility issues, and adverse events like dose-dependent thrombocytopenia (see Hafezi at p. 4 “3.1 ABT-737 and ABT-263 (Navitoclax)”). Hafezi also teaches that BCL-xL inhibitor AZD4320 while active in acute myeloid leukemia with reduced thrombocytopenia, faces challenges due to cardiovascular toxicity in preclinical studies which required polymer conjugation (AZD0466) to overcome (Hafezi at p. 5 ¶1).
The prior art provides enablement for treating BCL-xL-mediated diseases such as hematological malignancies. The prior art does not provide enablement for the full scope of diseases claimed, including treating or preventing all cancer or CNS diseases.
The amount of direction or guidance provided (5) and the presence or absence of working examples (6)
The specification provides the following embodiments:
BCL Inhibition assays, of the 87 species, 73 were tested for BCL-xL and BCL-2 inhibition, resulting in a range of IC50s (see instant spec. at pp. 157-163).
Cell proliferation assays, of the 87 species, 39 were tested against MOLT-4 cells (a T lymphoblast cell line derived from an acute lymphoblastic leukemia patient, as evidenced by U.S. Patent No. 10,363,247 B2 to Baloglu et. al.4 at col. 49) and 27 were tested against RS4;11 cells (an acute lymphoblastic leukemia cell line, as evidenced by Ragusa et. al.5 at p. 2 right col. ¶2) with a range of efficacy.
The specification provides enablement for treating a BCL-xL mediated disease such as a hematological malignancy.
Nowhere in the specification is it explained how such cancers or any other disease listed in claim 25 are to be prevented through the administration of the claimed compounds.
Therefore, the full scope of treatment in the methods of claim(s) x is/are not enabled.
The quantity of experimentation necessary (7) and the relative skill of those in the art (8)
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. Because of the unknown predictability in the art (as discussed above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that all compounds of Formula I could be used as treatments or preventions for all diseases specifically listed in claim 25.
As noted above, little experimentation provided is drawn to treatment, prevention, and prophylaxis of diseases listed in claim 25. A review of the state of the art fails to reveal that BCL-xL inhibitors are useful as therapeutic treatment as claimed (e.g. a CNS such as Alzheimer’s, all/any cancer, etc). Determining if compounds of Formula I would be therapeutic for any particular disease state would require careful analysis and replicability of a composition comprising a compound of Formula I, formulation into a suitable dosage form, assay testing to correlate clinical efficacy, identifying off-targets, subjecting to animal trials, and subjecting to clinical trials.
All this is undue experimentation given the limited guidance and direction provided by Applicants.
Conclusion
Accordingly, the invention of claim 25 does not comply with the enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Suggested Amendment
Examiner suggests amending claim 25 to read as:
Claim 25. A method for treating a BCL-xL mediated disease, wherein the BCL-xL mediated disease is selected from the list consisting of: solid tumors, hematological malignancies, virus infection, immune and inflammatory diseases, age-related diseases, or central nervous system-related diseases in a subject, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
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 7-8, 11 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 7, the phrases "preferably" and “more preferably” are recited and renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 8, the phrase "specifically" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 11, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Claims 14, 24 are 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.
Regarding claim 14, claim 1 recites “provided that at most one of X5, X6, X7, and X8 is not present.”
Claim 1
Formula I
Claim 14
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Claim 14 depends from claim 1, but recites a one ring moiety without any of X5-X8, thus broadening the scope of the claim from which it depends.
Regarding claim 24, claim 1 recites the genus of Formula I which contains a pyrazole ring. Claim 24, which depends from claim 1, recites species that do not belong to the genus of Formula I because they lack the pyrazole-L3-CyD moiety.
Claim 1
Formula I
Claim 24
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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 § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2, 7-8, 10-11, 13-14, 16, 20, 23, 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 20200199123 A1 to Starczynowski et. al.6
Claim interpretation: claims 13, 16, 20, and 23 are drawn to structural limitations that are not required, but if present are limited. Accordingly prior art that discloses species that do not comprise the relevant structural limitations read on these claims.
Regarding instant claims 1-2, 7-8, 11, 13-14, 16, 20, 23 and a compound of Formula I, Starczynowski teaches IRAK inhibitors of Formula I (see Starczynowski at p. 1) such as Compound I-6, also known as CAS# 1044733-13-2 (see Starczynowski at p. 13).
Starczynowski
Formula I
Starczynowski Compound I-6
CAS# 1044733-13-2
Instant Formula I
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CAS# 1044733-13-2 corresponds with instant Formula I when A is heterocyclyl specifically piperdine, L1 is -NRLa- and RLa is H, CyB is a divalent 6-membered heteroaryl group comprising 1 nitrogen specifically pyridine, L2 is a single bond, X1 and X2 are CH, X3 is N, X4 is C, X5 is N, one of X6 or X7 is absent and the other is CH, X8 is C, in otherwords
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moiety is
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, n is 0, p is 0, R4a is and R4b are H, L3 -C(RLaRLb)q and q is 1, RLa and RLb are H, CyD is H.
Regarding claim 25 and a method, Starczynowski teaches the disclosed compounds are IRAK inhibitors to be used in a combination with a BCL-2 inhibitor for treating acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin’s lymphoma, or Waldenstrom’s macroglobulinemia (see Starczynowski at claims 41, 57), reading on instant hematological malignancies. Starczynowski teaches administering disclosed compositions to an animal (see Starczynowski at claim 46).
Regarding claim 26 and a composition, Starczynowski teaches a pharmaceutical composition comprising the disclosed compounds, a BCL-2 inhibitor, and a formulatory agent, and adjuvant, or a carrier (see Starczynowski at claims 38-40), reading on instant excipient.
The prior art differs from the instant claims as follows: While Starczynowski teaches CAS# 1044733-13-2, CAS# 1044733-13-2 differs from instant formula I in that R3 is H and not a substituent listed in claim 1, such as a halogen, and from instant claim 10 in connectivity.
However,
Regarding H for halogen, Starczynowski teaches compounds of Formula I wherein R1 may be halogen, hydroxy, C1-C7 alkyl, C2-7 alkenyl, C2-C7 alkynyl, or C1-C6 alkoxy (see Starczynowski at p. 1). Stracynzowski teaches species wherein R1 is a halogen such as chlorine (see Starczynowski at p. 25 Compound I-62, at p. 26 Compound I-63).
Regarding claim 10 and an isomeric change, Starczynowski’s CAS# 1044733-13-2 pyridine moiety only differs from those instantly claimed in isomeric connectivity.
Starczynowski Compound I-6
CAS# 1044733-13-2 Pyridine
Instant Claim 10 Pyridines
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Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding H for halogen, per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would be obvious to an artisan to substitute the R1 position of CAS# 1044733-13-2 with a halogen such as chlorine in lieu of the hydrogen because the prior art teaches such a substitution is a suitable alternative to H at the same position.
Regarding isomer connectivity, per MPEP § 2144.09(I)-(II), “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities” because “[c]ompounds which are…isomers…are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties” (see, e.g., MPEP § 2144.09(I)-(II)), and the Court has stated that “[i]f a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 127 S.Ct. at 1740. Here, the prior art teaches highly similar structural isomers of the instantly claimed invention, wherein such isomers have the same, exact utility as the instantly claimed compounds; accordingly, an artisan would readily appreciate that such compounds could be utilized in the treatment of hematological malignancies exactly as taught and suggested in view of the prior art.
Furthermore, it is well-within the ordinary skill in art to incorporate chlorine in lieu of hydrogen on a known compound.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 1, 5, 10-11, 13, 16, 18-20, 23, 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008078100 A1 to Berdini et. al.7 in view of Wermuth et. al.8
Claim interpretation: claims 13, 16, 20, and 23 are drawn to structural limitations that are not required, but if present are limited. Accordingly prior art that discloses species that do not comprise the relevant structural limitations read on these claims.
Regarding claims 1, 5, 10, 13, 16, 18-20, 23 and a compound of Formula I, Berdini teaches modulators such as Example 14, also known as CAS# 1036761-47-3 (see Berdini at p. 135).
Berdini Example 14
CAS# 1036761-47-3
Instant Formula I
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CAS# 1036761-47-3 corresponds with instant Formula I when A is a 5-membered heteroaryl comprising 3 heteroatoms S, N, N, specifically 1,3,4-thiadiazole, L1 is NRLa and RLa is hydrogen, Cyb is a divalent aryl group specifically unsubstituted 1,3-phenylene
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, X1-X3 are C, X4 is N, one of X5-X8 is absent and the remaining are C, C, and N, L2 is a bond, L3 is a -C(RLaRLb)q, q is 1, RLa is H, RLb is h, CyD is H, R4a and R4b are H, n is 0, p is 0, m is 0.
Regarding claim 25 and a method of treating, Berdini teaches FGFR or VEGFR or PDGR modulators (see Berdini at p. 66 ¶3) for treating cancers, such as hematopoietic tumors of lymphoid lineage such as leukemia (see Berdini at p. 69 ¶1, p. 73 ¶5). Berdini teaches administering the disclosed compounds to a subject (see Berdini at p. 74 ¶9).
Regarding claim 26 and a composition, Berdini teaches formulating the disclosed compounds with a carrier, excipient, buffer, adjuvant, or stabilizer to form a pharmaceutical composition (see Berdini at p. 77 ¶7).
The prior art differs from the instant claims as follows: While Berdini teaches CAS# 1036761-47-3, CAS# 1036761-47-3 differs from the genus of Formula in that R3 is H, and not a substituent listed in claim 1, such as a halogen.
However,
Regarding claims 1, 11, and halogen vs hydrogen, Wermuth teaches fluorine for hydrogen isosterism often improves compounds in regards to metabolic degeneration (see Wermuth at p. 227 "(b) Electronic aspects").
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding fluorine for hydrogen, per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to an artisan to substitute a hydrogen for a fluorine on a known compound (e.g. CAS# 1036761-47-3 as taught by Berdini) with a reasonable expectation of success because the prior art teaches such a change improves metabolic degradation (as taught by Wermuth).
Furthermore, it is well-within the ordinary skill in art to incorporate fluorine in lieu of hydrogen on a known compound.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Allowable Subject Matter
Claims 12 and 22 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 15 and 24 are currently objected to or rejected under 35 USC 112, and are dependent upon a rejected base claim, but would be allowable if the outstanding objections and rejections resolved, and rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1, 12, 15-16, 22, 25 are objected to.
Claims 1-2, 5, 7-8, 10-11, 13-14, 16, 18-20, 23-26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
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/SOPHIA REILLY/Examiner, Art Unit 1627
1 Meyskens et. al. “Cancer Prevention: Obstacles, Challenges, and the Road Ahead” J Natl Cancer Inst 2016, 108, 2, djv309, 1-8. DOI: 10.1093/jnci/djv309. Hereinafter Meyskens.
2 Danon et. al. "Challenges and Opportunities in Central Nervous System Drug Discovery" Trends in Chemistry, 2019, 1, 6, 612-624. DOI: 10.1016/j.trechm.2019.04.009. Hereinafter Danon.
3 Hafezi et. al. "Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives" Cancers 2021, 13, 6, 1292, 1-15. DOI: 10.3390/cancers13061292. Hereinafter Hafezi.
4 Patented July 30, 2019. Hereinafter Baloglu.
5 Ragusa et. al. "The RS4;11 cell line as a model for leukaemia with t(4;11)(q21;q23): Revised characterisation of cytogenetic features" Cancer Rep, 2019, 2, 5, e1207, 1-11. DOI: 10.1002/cnr2.1207. Hereinafter Ragusa.
6 Published June 25, 2020. Hereinafter Starczynowski.
7 Published July 3, 2008. Hereinafter Berdini.
8 Wermuth, Camille. “Molecular Variations Based on Isosteric Replacements” in The Practice of Medicinal Chemistry, 1st ed., Academic Press, 1996, pp.203-237. Hereinafter Wermuth.
