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 .
Detailed Action
Filing Receipt and Priority
The filing receipt mailed 04/29/2024 states that the instant application is a 371 of PCT/IN2022/050513, filed 06/02/2022, which claims foreign benefit of INDIA 202111024755, filed 06/03/2021.
The certified copy of the foreign application received 11/30/2023 supports the instant application. Therefore, the effective filing date is 06/03/2021.
Information Disclosure Statement
The information disclosure statement submitted 11/27/2024 has been considered.
Species Election
Applicant’s election of compound of Example 38 in the remarks submitted 04/30/2026 are acknowledged. Search and examination has been broadened to the full scope of claim 1.
Objections
Specification
The instant disclosure refers to an “azido ester compound of formula (4)”. The drawing contains the following formula.
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“R” is not explicitly defined, and critically, there is only one specific azido ester disclosed within the specification which is methyl azidoacetate.
See 112(b) rejection below.
Claim Objections
Claim 1 is objected to for the following errors:
The term “X3” is repeated where it is clear applicant intended “X4”.
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Similar issue is found with the term “C3-8 cycloalkyl” in bullet iii of claim 1.
Claim 1 under the listing of potential substituents for R3 states “caboxy” where it should state “carboxy”.
Claim 2 is objected to for the use of bullets (“1., 2., 3., etc.”) in the claim. The MPEP section 608.01(m) states “Periods may not be used elsewhere in the claims except for abbreviations.”
Claim 3 is objected to for the use of backslashes (“/”) in the claim. Claim 3 states “Vilsmeier Haack reagent/adduct”. Typically, the use of the backslash is drawn to ratios or when using “and/or”. It is clear applicant intends to state “Vilsmeier Haack reagent and/or adduct”. The claim would be in better form if amended. Similar issues are found in bullet vi of claim 3 “aryl/heteroaryl”
Claim 3 in bullet v states “using halogenated reagents” where it should state “halogenating reagents”.
Claim 3 in bullet viii states “wherein R1 is same as defined above” where it should state “wherein R1 is same as defined in claim 1”.
Rejections
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 9 and 10 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 methods of treating bacterial infections caused by Klebsiella pneumoniae comprising administering synergistic combinations of compounds 1-74 and imipenem and/or meropenem, does not reasonably provide enablement for methods of treating all bacterial infections using all compounds represented by Formula I in claim 1. 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.
The following Wands Factors have been considered if not explicitly stated:
(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.
Breadth of the claims
Claim 9 is drawn to a method of treating bacterial infections comprising administering a pharmaceutical composition of claim 5.
Claim 5 is drawn to a pharmaceutical composition comprising the compound of formula I and an excipient.
Formula I is shown below.
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The full scope of claim 1 includes compounds with substantial additional substitution at positions R1-R11. A specific example is that the substituents R8-R9 and R10-R11 can form spirocyclic ring systems at their respective positions. Substituents R3-R7 include alkyl groups, aryl groups, heteroaryl and heterocyclyl groups that are further substituted with additional alkyl groups, aryl groups, heteroaryl and heterocyclyl groups. The full scope of R1 includes hydroxyl, amines, esters, and alkyl groups that would lead to aldehyde or ketone moieties. The full scope of R2 would place significantly large unsubstituted and substituted alkyl groups around the ring system.
“Bacterial infection” is not defined. The broadest reasonable interpretation is then drawn to all bacterial infections which includes Gram-positive and Gram-negative bacteria. The term also includes strains of bacteria which are resistant to Imipenem and meropenem.
Critically, the claimed method only requires administration of a composition comprising the compounds of formula I.
Claim 10 further includes a “beta-lactam antibiotic” which is not specified.
Nature of the invention
Claims 9 and 10 are drawn to a clinical method.
State of the prior art
A search did not result in any art that could be applied to claims 1 or 2. Therefore, any efficacy of the instant compounds is available only through the instant disclosure.
The art does disclose administration of imipenem and meropenem, as discussed in Balfour (Drugs 51, 99–136 (1996)) and Edwards (Journal of Antimicrobial Chemotherapy, 1995, 36, Suppl. A. 1-17) respectively. Both imipenem and meropenem are known as broad spectrum antibiotics, Imipenem is known to have efficacy against Gram-negative bacteria and many Gram-positive bacteria. However, imipenem activity against methicillin-resistant strains of S. aureus, penicillin-intermediate and resistant strains of S. pneumoniae, coagulase-negative staphylococci and Enterococcus faecalis (Balfour, sec. Antibacterial activity). Similarly, Edwards in its abstract states “Meropenem is a parenteral carbapenem antibiotic which has excellent bactericidal activity in vitro against all clinically significant aerobes and anaerobes.”
However, neither imipenem or meropenem are required by claim 9 or required in the composition of claim 5.
One of ordinary skill
One of ordinary skill would be a trained medicinal chemist and/or clinical doctor which includes advanced education and an advanced skillset.
The amount of direction and working examples
The instant specification discloses IC50 data for compounds 1-30 against New Delhi metallo-β-lactamase (NDM-1) and IMP-1. (See table below)
The instant specification on p. 1, l. 25-p. 2, l. 2 discusses β-lactamase enzymes. The specification states “Among Gram-negative bacteria, there are four classes of beta-lactamases, the serine beta-lactamase (SBLs) of the classes A, C and D, and the MBLs (class B). SBL enzymes uses active serine present in its catalytic site to hydrolyse the β-lactam rings in a covalent mechanism whereas MBL enzymes requires Zn metal which helps in coordination and a hydroxide ion to hydrolyze the β-lactam ring….The zinc-dependent class B metallo-beta-lactamases are represented mainly by the NDM, VIM, and IMP types.”
Combined with the IC50 data below, the instant disclosure shows that the instant compounds have efficacy in inhibiting the NDM-1 and IMP-1 enzymes. However, the compounds were not administered by themselves to treat bacterial infections.
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The instant specification does disclose administration of a number of compounds of the instant formula I along with imipenem and meropenem against the Klebsiella pneumoniae strain of bacteria. Compounds 2, 34-39, 41-54, 56-64 were tested in combination with either imipenem or meropenem. Results are disclosed in sec. Checkerboard synergy assay, specifically table 2 of the specification. The table supports a synergistic effect when either imipenem or meropenem are administered with the compounds tested. However, no other beta-lactam antibiotics were tested and the only strain of bacteria tested against is the K. pneumoniae strain. These are non-representative examples of their full genera.
Further, the compounds tested are not representative of the full scope of the compounds claimed. As stated in the breadth of the claim section, the full scope of Formula I reaches well beyond what has been tested. None of the test compounds include complicated branching alkyl chains, spirocyclic ring systems, amides, aldehydes or ketones. Applicant is enabled only for compounds 1-75.
Level of predictability and Quantity of Experimentation
While the art regarding imipenem and meropenem is well known, the combination of the two with the instant compounds is not as well known. Additionally, the two antibacterial compounds are broad spectrum antibiotics with variable efficacy against certain strains.
Additionally, the claimed compounds serve as effective metallo-β-lactamase inhibitors. Their efficacy against other classes of β-lactam antibiotics is unknown.
Critically, there is no evidence within the specification that the methods would function as claimed, which comprises administering the compounds of Formula I as monotherapy. Effective treatment against the specific strain of bacteria requires the inclusion of imipenem or meropenem with the enabled compounds of formula I.
Therefore, the is a significant level of unpredictably should one of ordinary skill attempt to practice the claimed methods to their full scope.
Written Description
Claims 1 and 3 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.
Claim 1 states “’n’ is an integer ranging from 0 to 5, both inclusive;”.
“n” within the structure below can, at max, only be 4.
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Claim 3 recites the following.
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“R1” is defined in claim 1 as:
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.
First, as “R1” encompasses more than just a hydroxyl group, the conversion of the compound of formula Ia to the full scope of R1 is not possible with a simple hydrolysis. Additionally, in the interpretation that R1 is an amide or ester, one of ordinary skill cannot further convert an amide or ester to itself. The current method cannot function as claimed.
It is suggested that applicant either amend the claim so that the structure instead shows a carboxylic acid group or amend the claim language of bullet vii to incorporate the claim language of bullet viii as an optional step to arrive at the compound of formula I.
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, 3, 5-6, and 9-10 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 term “substituent groups” in bullet iii of claim 1 is not defined in the claim or in the specification. In the chemical arts “substituent group” may refer to any potential variable group that may replace a hydrogen atom among the compound structure. Because the term is not defined, one of ordinary skill in the art would not know which specific groups are encompassed by “substituent groups”.
Additionally, claim 1 in bullet ii states:
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Ra and Rb are not bonded to a carbon atom. The claim is indefinite because one of ordinary skill in the art would not know the structure that is being claimed.
As claim 5 incorporates the compound of claim 1, it is also rejected.
Claim 3 uses the term “such as” which causes the claim to be indefinite because it is not clear if applicant is claiming the limitations after the recitation of “such as”. Claim 3 additionally uses the term “etc.” which is indefinite because “etc.” is not an explicit recitation of limitations.
Claim 3 recites the “suitable Lewis acid”. Here, “suitable” is a relative term and is indefinite because applicant is not explicitly claiming specific Lewis acids. “Suitable” is not defined and one of ordinary skill in the art is not enabled to determine which Lewis acids are “suitable” or not.
Claim 3 uses the clam language “azido ester compound of formula (4)” in bullet iii. The formula is not defined in the claim or specification. The drawing contains the following formula.
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Additionally, claim 3 uses the undefined “R” group as shown below.
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“R” is not explicitly defined, and critically, there is only one specific azido ester disclosed within the specification which is methyl azidoacetate. The claim is essentially referring to the drawing and also refers to a formula that is not clearly defined (“R”). While the specification is used to determine the meaning of claim language, it is improper to read the specification into the claim. Therefore, the claim is indefinite.
Claim 6 states “The pharmaceutical composition of claim 5, wherein said composition further comprises an effective amount of a beta-lactam antibiotic.” The term "effective amount" is indefinite where the claim fails to state the function which is to be rendered effective. See In re Frederiksen, 102 USPQ 35 (CCPA 1954).
Claims 9 states “A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 5. Claim 5 states “A pharmaceutical composition comprising at least one compound of Formula (I) or salt thereof, according to claim 1 and a pharmaceutically acceptable excipient”. Claim 9 lacks “an effective amount” with which one of ordinary skill would be able to treat a bacterial infection.
Similarly, claim 10 also lacks an “effective amount” of the beta-lactam antibiotic.
Note: The instant specification on p. 13-14 makes a distinction between “effective amount” and “therapeutically effective amount”. The specification gives “inhibiting MBL” as an example of an “effective amount”. A “therapeutically effective amount” is defined as “the amount of a compound that, when administered to a subject for treating a disease, disorder or condition, is sufficient to cause the effect in the subject, which is the purpose of the administration.” An “effective amount” does not necessarily lead to treatment.
Allowable Subject Matter
Claim 2 is 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.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUISALBERTO GONZALEZ/Examiner, Art Unit 1624
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