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 Application
The amendment of 21 November 2023 is entered.
Claims 15-17 have been canceled. Claims 1-14 and 18-21 are pending and are being examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim Interpretation
Claims 1 and 8 recite in the preamble that the composition is “for treating or preventing a bacterial infection caused by tuberculosis bacteria or nontuberculosis mycobacteria” or “for treating or preventing a bacterial infection caused by clostridium bacteria”.
In both instances, the claim language is treated as a recitation of intended use. Per MPEP 2111.02, preamble statements reciting intended use are only considered to be a patentable limitation when they result in a structural difference. In this case, the body of both claims 1 and 8 recite the pharmaceutical composition, the form of the composition, and the effective component in the form of Chemical Formula 1. In neither claim does the intended use result in a structural difference. As a result, the intended uses are considered for the purposes of 35 U.S.C. 112 but are not considered a limitation for the purposes of 35 U.S.C. 101 or prior art rejections under 35 U.S.C. 102 or 103. The dependent claims further limiting the intended use, i.e. claiming of a specific bacterium, likewise are not considered to be patentable limitation.
If the Applicant desires to claim a method of treating or preventing these bacterial infections, such claims may be added in response to this Action but will likely be treated as withdrawn through election by original presentation in accordance with MPEP 821.03.
Claim Objections
Claim 8 is objected to because of the following informalities: the compounds ethionamide, imipenem, and cilastatin are each claimed twice. Appropriate correction is required.
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 1-14 and 18-21 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.
The claims recite a composition of chemical formula I that also encompasses solvates, hydrates, and prodrugs.
The specification does not offer particular guidance on solvate forms. The term is defined as “the micrococcin compound of the present invention of a pharmaceutically acceptable salt thereof, including a stoichiometric amount or non-stoichiometric amount of solvent bound by non-covalent intramolecular force”. No actual solvate forms are disclosed.
Likewise, hydrates are defined as “the micrococcin compound of the present invention of a pharmaceutically acceptable salt thereof, including a stoichiometric amount or non-stoichiometric amount of water bound by non-covalent intramolecular force”. No actual hydrates are disclosed.
Prodrugs are defined as “the micrococcin compound of the present invention which may be hydrolyzed, be oxidized, and cause a different reaction under biological conditions (in vitro or in vivo) for supplying an active compound, in particular, the micrococcin compound of the present invention”. No actual prodrug forms are disclosed.
The artisan understands the concept of prodrugs, however the artisan does not per se understand what specifically describes a specific prodrug form. For example, for an ester prodrug, the general formula may be applied: Drug-C(O)O-R or Drug-OC(O)-R, where R is, as in the instant case, an unknown moiety that is to be determined to provide the necessary properties of an ester prodrug. Further, where to place this unknown moiety is also an essential teaching that must be known to the skilled artisan in the making and using of the claimed invention.
(A) The art acknowledges there is no specific definition for prodrug (e.g. page 1, HAN, H.-K.. AAPS Pharmsci. (2000) 2(1), article 6, pages 1-11, but that in general, the 'prodrug' is an inactivated form of the drug that activates in vivo to the active form. While some prodrugs are simply esters or salts, other prodrug forms are not chemically or structurally related to their active form, one example being glucose as the prodrug form of hydrogen peroxide (Table 1, page 5), as is hypoxanthine, thus posing a problem as to understanding what is the exact prodrug form of a compound, as hydrogen peroxide has two prodrug forms in the limited set of compounds exemplified in Han.
(B) Beaumont, et al. “Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist,” Current Drug Metabolism, 2003, 4, 461-485, states that “the rationale behind the prodrug strategy is to introduce lipophilicity and mask hydrogen bonding groups of an active compound by the addition of another moiety, most commonly an ester. An ideal ester prodrug should exhibit the following properties:
1) Weak (or no) activity against any pharmacological target,
2) Chemical stability across a pH range,
3) High aqueous solubility,
4) Good transcellular absorption,
5) Resistance to hydrolysis during the absorption phase,
6) Rapid and quantitative breakdown to yield high circulating concentrations of the active component post absorption. The major aim of a prodrug approach is to mask polar or ionisable groups within a molecule. This increases the overall lipophilicity of the molecule and promotes membrane permeability and oral absorption. However, increases in lipophilicity produced by a prodrug approach do not inevitably lead to major improvements in oral bioavailability. This is due to the multiplicity of the barriers facing oral delivery. These are outlined in Fig. (1) of the article.
Further, there are four main chemical factors to be taken into account when designing an ester prodrug, the most common form:
1) Sufficient stability to enable synthesis, purification and
2) Sufficient aqueous solubility to allow complete oral absorption.
3) Greater bioconversion rate in tissue or blood compared to hydrolysis in aqueous solution at physiologically relevant pH.
4)The liberated fragments of the hydrolysis must have low toxicity and no unwanted pharmacology.
When present in a commercially viable pharmaceutical product, an ester needs to be sufficiently stable to enable the chemical synthesis, isolation and purification of the drug substance. This material also needs to be stable to formulation into the final drug forms, such as tablets, capsules, syrups, solutions (aqueous and organic) and ointments, and with sufficient stability to have an appropriate ‘shelf-life’. Beaumont, et, al concludes: “Clearly, prodrug strategies have been successful for a number of important therapeutic agents. However, further investigation suggests that the hurdles to oral delivery of an ester prodrug are not trivial. These include maintaining sufficient aqueous solubility, lipophilicity and chemical stability at the same time as enabling rapid and quantitative release of active principle post absorption. In addition, significant nonesterase metabolism and transporter mediated clearance of the prodrug is not desirable. For these reasons, it appears that achieving high oral bioavailability values with a prodrug approach is extremely difficult and a realistic target for oral bioavailability would be 50%. In addition, designing an ester prodrug that balances all of these issues is a difficult undertaking and a robust screening sequence is required in the Discovery environment. However, due to the difficulty in predicting the human disposition of an ester prodrug, it may be necessary to evaluate several examples in human pharmacokinetic studies. Given the complexities outlined in this review, it is recommended that the prodrug strategy is only considered as a last resort to improve the oral bioavailability of important therapeutic agents.”
None of these principles or properties have been demonstrated in any compound claimed or found in the specification.
(C) Muller, Christa E. “Prodrug Approaches for Enhancing the Bioavailability of Drugs with Low Solubility,” Chemistry & Biodiversity, Vol. 6 (2009), pages 2071-2083 teaches “the interest in prodrugs has exponentially grown over the past 20 years as shown by the increasing number of publications (see Fig. 1). In 2008, 26 new drugs reached the German market (for information see: http://www.pharmazeutische-zeitung.de/index.-php?id¼2670). Of these 26 new drugs, 21 were small molecules, and four were macromolecules including biologicals, polymers, or oligomers. Four or 15% of all drugs (corresponding to 19% of the small molecules) were prodrugs (see Fig. 2). Further, the 100 blockbuster drugs can be divided into 22 biologicals and 78 small molecules. Of the small molecules, 12% can be classified as prodrugs if a conservative prodrug definition is applied (excluding, for example, nucleoside analogs which have to be transformed to the corresponding triphosphates in order to exert their antiviral activity).” In short, prodrugs remain a very small population of the most popular drugs on the market. More importantly, Muller concludes, “We are just at the beginning of a new “prodrug era,” which indicates that much is still learn and remains unpredictable in light of the previous review articles.
(D) Singh, Yashveer et al, “Recent Trends in Targeted Anticancer Prodrug and Conjugate,” DesignCurr Med Chem. 2008 ; 15(18): 1802–1826, teaches
“It must be accepted that overall success achieved so far with targeted prodrug design is far from satisfactory. Only a limited number of prodrugs have been approved so far despite the fact that fairly large numbers of prodrugs undergo clinical trial every year. The limited clinical success of targeted prodrug design could be attributed to several factors. Prodrug design is often an afterthought, which is implemented when a particular drug shows undesirable pharmacokinetic and pharmacodynamic properties. We believe that more successful prodrugs are likely to reach the market if prodrug design is incorporated upon inception of a new therapeutic.”
“The preclinical evaluation of prodrugs relies mostly on mouse models with human transplanted tumors. Prodrugs found to be effective in such models are moved into the clinical trials. These models though useful cannot account for species specificity. The development of new and dynamic animal models more reflective of human disease states is a major challenge in targeted prodrug design, as it is any other drug design.”
“Design of targeted prodrug involves conjugation of active drug to carrier molecules such as sugars, growth factors, vitamins, antibodies, peptides and synthetic polymers through a linker.”
“Optimization of synthetic procedure is a major challenge as the chemistries associated with drug molecule and the carrier may not always be compatible. There is a possibility that the carrier may induce immunogenic responses and/or increase the lipophilicity upon conjugation.”
“An unbalanced increase in lipophilicity may reduce the aqueous solubility and therefore the drug bioavailability. Attachment to the carrier also influences the drug stability and activity and any undesirable change may compromise the clinical efficiency of the prodrug. The amount of drug that can be attached to the carrier (drug loading) is often limited due to the number of attachment sites available. The drug loading remains a major impediment to clinical success of targeted prodrug design as it determines the amount of drug reaching the target site. The drug loading can be augmented by using multiple copies drugs. Attachment of multiple drug copies can improve the in vitro drug activity but this may not necessarily translate into increased therapeutic benefit. There is a need to correlate drug loading with corresponding clinical efficacy.”
“A major concern in targeted prodrug design is the fact that the targeting strategies are based on the assumption that a particular enzyme or receptor is elevated in tumor tissues. The prodrugs that are converted to active drug by tumor-associated enzymes or internalized by binding to receptors should improve the therapeutic index. However, normal tissues or organs can express the same enzymes endogenously, thus there is a possibility of off target effects.”
“This problem is further compounded by the fact that tumors are heterogeneous, therefore their enzyme expression profiles are variable. Consequently, prodrug designed for particular tumor associated enzyme may undergo differential activation in tumors or may not be activated at all thereby influencing the therapeutic efficacy. The choice of appropriate target antigen and/receptor is key to efficient targeted prodrug design.”
“The strategies we have described in this review range from simple modifications to complex systems involving several pharmaceutical and biological manipulations. However, the greatest benefit of prodrug design is the flexibility in it techniques and components. The development so far are significant and they are expected to provide framework for future research efforts in targeted prodrug design, which in turn will lead to the development of some useful anticancer prodrugs and conjugates. As the field grows, and new polymers, antibodies, targets, are identified, prodrug design is expected to become the norm in therapeutics instead of the afterthought.”
(E) and (F) Ettmayer P. et al. J. Med. Chem. (2004) 47(10), pages 2393-2404), prodrugs are often accidental discoveries and Testa. Biochem. Pharm. (2004) 68, pages 2097-2106 teaches that, "A number of challenges await medicinal chemists and biochemists carrying out prodrug research, such as the additional work involved in synthesis, physicochemical profiling, pharmacokinetic profiling and toxicological assessment. Two of these challenges are introduced here, namely biological variability and toxicity potential. The challenge of biological variety results principally but not only from the huge number and evolutionary diversity of enzymes involved in xenobiotic metabolism. Inter- and intra-species differences in the nature of these enzymes, as well as many other differences such as the nature and level of transporters, may render prodrug optimization difficult to predict and achieve." (page 2098).
The few exemplary journal articles presented here show an inherent unpredictability in making and using prodrugs that have been experienced in the past and are still prevalent today. The six factors of
1) Weak (or no) activity against any pharmacological target,
2) Chemical stability across a pH range,
3) High aqueous solubility,
4) Good transcellular absorption,
5) Resistance to hydrolysis during the absorption phase,
6) Rapid and quantitative breakdown to yield high circulating concentrations of the active component post absorption remain discoverable and not even remotely addressed in the specification. The unpredictability of making and using prodrugs is reflected in the rather small percentage of compounds that are in current use as prodrugs in the market as well as the large number of compounds that fail in clinical trials, reflected in the references supra. Given that Applicants have not provided any ground work or examples of prodrug beyond a listing of general references, one is left with the burden of trial and error of
(1) guessing what ester moiety to make or other prodrug form to try next, and
(2) guessing where to place the ester or prodrug moiety on the molecule.
The lack of guidance in the specification leaves the six factors disclosed by Beaumont et al left to trial and error, and the prior art shows it is statistically mostly error in the making and using.
Namely, as to solvates (and/or hydrates) of the compounds claimed.
VIPPAGUNTA (Vippagunta, et al. Adv. Drug Delivery Rev. (2001) 48, pages 3-26) teaches that, "The common crystalline forms found for a given drug substance are polymorphs and solvates. Crystalline polymorphs have the same chemical composition, but different internal crystal structures, and therefore, possess different physico-chemical properties." (page 4).
“Solvates, also known as pseudopolymorphs, are crystalline solid adducts containing solvent molecules within the crystal structure, ... giving rise to unique differences in the physical and pharmaceutical properties of the drug. If the incorporated solvate is water, a solvate is termed a hydrate." (page 4).
Vippagunta teaches that, "Because different crystalline polymorphs and solvates differ in crystal packing, and/or molecular conformation as well as in lattice energy and entropy, there are usually significant differences in their physical properties, such as density, hardness, tabletability, refractive index, melting point, enthalpy of fusion, vapor pressure, solubility, dissolution rate, other thermodynamic and kinetic properties and even color. Differences in physical properties of various solid forms have an important effect on the processing of drug substances into drug products, while differences in solubility may have implications on the absorption of the active drug from its dosage form, by affecting the dissolution rate and possibly the mass transport of the molecules." (page 4).
Vippagunta teaches that, "It is very important to control the crystal form of the drug during the various drug development, because any phase change due to polymorph interconversions, desolvation of solvates, formation of hydrates and change in the degree of crystallinity can alter the bioavailability of the drug. When going through a phase transition, a solid drug may undergo a change in its thermodynamic properties, with consequent changes in its dissolution and transport characteristics." (page 5).
Vippagunta teaches that there are reversible and irreversible polymorphs (page 6), and polymorphs which are structural or conformational polymorphs (pages 7-11). Vippagunta further teaches that, "The main challenge in managing the phenomenon of multiple solid forms of a drug is the inability to predict the number of forms that can be expected in a given case." (page 11).
Vippagunta teaches that "Phase changes due to hydration/dehydration and solvation/desolvation of pharmaceutical compounds during processing or in the final product may result in an unstable system that would effect the bioavailability of drug from solid dosage forms. Various types of phase changes are possible in solid-state hydrated or solvated systems in response to changes in environmental conditions... For example, some hydrated compounds may convert to an amorphous phase upon dehydration and some may convert from a lower to a higher state of hydration yielding forms with lower solubility. Alternatively, a kinetically favored but thermodynamically unstable form may be converted during pharmaceutical processing to a more stable and less soluble form." (page 17).
Vippagunta teaches that, "Predicting the formation of solvates or hydrates of a compound and the number of molecules of water or solvent incorporated into the crystal lattice of a compound is complex and difficult Each solid compound responds uniquely to the possible formation of solvates or hydrates and hence generalizations cannot be made for a series of related compounds... There may be too many possibilities so that no computer programs are currently available for predicting the crystal structures of hydrates and solvates." (page 18).
The prior art casts doubt on both prodrug forms as well as solvates/hydrate forms of peptide drugs.
There is no clear reduction to practice of any solvate, hydrate, or prodrug forms of Chemical Formula I as claimed.
Based on the generic guidance provided, lack of predictability based on the prior art, and failure to disclose or suggest any particular forms for any solvates, hydrates, or prodrugs of Chemical Formula I, one of ordinary skill in the art would not recognize possession of the invention as claimed. Therefore, written description is lacking.
Claims 1-21 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 isomers and pharmaceutically acceptable salts of Chemical Formula 1, does not reasonably provide enablement for solvates, hydrates, or prodrugs thereof. 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 the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). 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 USPQ2sd 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). Among these factors are:
(1) the nature of the invention;
(2) the breadth of the claims;
(3) the state of the prior art;
(4) the relative skill of those in the art;
(5) the predictability or unpredictability of the art;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to solvates, hydrates, prodrug, and isomer forms of the Chemical Formula I. Thus, the claims taken together with the specification imply untold number of chemical modifications that are alleged to convert the compound in to a solvate, hydrate, or prodrug form.
(3) The state of the prior art:
As noted above, the prior art casts significant doubt on solvate, hydrate, and prodrug forms of drugs.
4) The relative skill of those in the art:
The level of skill to practice the art of the instantly claimed invention, or any invention of pharmaceutical compositions constructed into a solvate, hydrate, or prodrug form is high with regard to first making the base compound and then considering what constitutes the solvate, hydrate, or prodrug form for the intended routes of administration. Compound synthesis, isolation, purification, and formulation for different routes of administration are a part of the process, and generally constitute multiple disciplines at that are not found in a single skilled artisan. Further, the bioassays and animal models that are needed to make a solvate, hydrate, or prodrug complicate what constitutes a solvate, hydrate, or prodrug for any specific compound and add additional skills and artisanal knowledge that demonstrate the complexity of the structure/function relationships in solvates, hydrates, and prodrugs. Thus, in the making and using of a solvate, hydrate, or prodrug, multiple skills from multiple skilled artisans are required.
(5) The predictability or unpredictability of the art, (6) The amount of direction or guidance presented, and (7) The presence or absence of working examples:
Since the information essential for making and using solvate, hydrate, or prodrugs of the compounds instantly claimed, and remains largely unsolved, means for producing a working example, let alone the full breadth from an extremely large genus of compounds claimed by the generic solvate, hydrate, and prodrug language, is highly unpredictable to even arrive at one claimed compound, and imagined for the entire genus of compound. The specification has provided information common to the skilled artisan in making pharmaceutically acceptable salts, or compositions of the compounds of the claim examined on the merits, but the specification does not provide any specific guidance for making any solvate, hydrate, or prodrug forms of the compounds as the specification merely references what might be done in an unpredictable “art” of making and using these forms.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the factors above, and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to make compounds by trial and error for routes of administration undisclosed in hopes of making a solvate, hydrate, or prodrug. Further, given the variance in the efficacy, absorption, and other important biophysical properties of the various species already made and assayed, the specification does nothing to inform what moieties could be selected for the solvate, hydrate, or prodrug forms to improve their properties as discussed above in references (A)-(F) and Vippagunta, leaving the whole of the various forms of Chemical Formula I left to chance and not to specific teachings and guidance from the specification or the references therein.
It is the Examiner’s position, based on the teaching of the prior art, that one skilled in the art could not practice the invention commensurate in the scope of the claims without undue experimentation.
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.
Claim 10 is 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 claim recites that the bacterial infection is diarrhea. Diarrhea is generally not understood to be a bacterial infection, although infection can cause diarrhea.
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.
Claims 1-5, 8-14, and 18-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception in the form of a natural phenomenon without significantly more. The claim(s) recite(s) pharmaceutical compositions comprising Chemical Formula I.
Chemical Formula I comprises the structure of micrococcin P2. The Applicants admit in [10] that micrococcin is a natural product that includes micrococcin P2. The Applicants further admit that micrococcin exists as P1 and P2 isoforms at 7:1 in Bacillus pumilus in [12]. Further evidence that Chemical Formula I exists in nature is found in Bycroft B and Gowland M (J.C.S. Chem. Comm. 1978, 256-278, published 1978, hereafter referred to a Bycroft) and Acker et al. (J. Am. Chem. Soc. 131:17563-17565, published 2009, hereafter referred to as Acker).
As noted above, claims 1 and 8 recite a pharmaceutical composition and include an intended use in the preamble, which is not viewed as a limitation of significance to claim construction for the purposes of 35 U.S.C. 101.
This judicial exception is not integrated into a practical application because there is no practical application claimed, only an intended use that is not treated as a claim limitation. See also MPEP 2106.04(d)(2).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements. The recitation of particular infections or bacteria are merely refinements of the intended use, and as noted above are not a claim limitation nor can these be considered a practical application that distinguishes from the natural product. Claim 18 recites an anti-inflammatory composition, but this also is merely linking a judicial exception to a particular technological environment. See MPEP 2106.05(e). Claims 14, 19, and 21 recite particular amounts of the compound, but again this does not distinguish from the judicial exception or offer a particular treatment or prophylaxis.
Since the claims are determined to be drawn to a judicial exception in the form of a natural phenomenon, are not integrated into a practical application beyond generic linkage to a technological environment, and not include additional elements to amount to significantly more than the judicial exception, they are ineligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
1. Claims 1, 3-5, 8, 10, 11, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bycroft B and Gowland M (J.C.S. Chem. Comm. 1978, 257-258, published 1978).
The Bycroft art discloses the structure of the antibiotic peptide micrococcin P2, which implies pharmaceutical use (see e.g. p.258 Col.2). As noted above, the intended uses of claims 1 and 8 are not considered claim limitations. This anticipates claims 1 and 8, as it contains a compound matching Chemical Formula 1.
With respect to claims 3-5 and 10-11, as noted above the limitations contained therein are all concerning the intended use, which as noted above is not of significance to claim construction. Accordingly, these limitations are also not of significance to claim construction, and Bycroft anticipates the claims.
With respect to claim 18, the preamble statement that the composition is an anti-inflammatory composition does not distinguish from the Bycroft art. Furthermore, any anti-inflammatory activity is inherent to the micrococcin P2, as a compound and its properties cannot be separated. See MPEP 2112, as well as Son et al. J. Natural Products 85:1928-1935 as establishing the anti-inflammatory activity.
2. Claims 1, 3-5, 8, 10, 11, 13, 18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Acker et al. (J. Am. Chem. Soc. 131:17563-17565, published 2009).
The Acker art discloses the structure of thiocillin antibiotics, including structures that encompass the claimed Chemical Formula 1 (see e.g. Figure 1, where R1=H, R2=H, and R3=CH2-C(O)-CH3). Acker notes wild-type thiocillins as being isolated and used to inhibit growth of B. subtilis and methicillin-resistant S. aureus, i.e. pharmaceutical compositions (see e.g. Table 1). This anticipates claims 1 and 8.
With respect to claims 3-5 and 10-11, as noted above these are treated as limitations to the intended use and are not considered to be of significance to claim construction.
With respect to claims 13 and 20, the use of the compounds for efficacy tests implies presence of a carrier.
With respect to claim 18, while Acker does not disclose anti-inflammatory activity, again this represents an inherent property of Chemical Formula I as noted above.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claims 2, 9, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Bycroft B and Gowland M (J.C.S. Chem. Comm. 1978, 257-258, published 1978) OR Acker et al. (J. Am. Chem. Soc. 131:17563-17565, published 2009) as applied to claims 1, 8, and 18 above, and further in view of Kazuma et al. (CA 2440353 A1, published 19 September 2002, hereafter referred to as ‘353).
The relevance of Bycroft and Acker are set forth above. The difference between the prior art references and the claimed invention is that neither discloses or suggests Chemical Formula 2.
The ‘353 art discloses thiocillin compounds including micrococcin P2 as in Bycroft and Acker (see e.g. p.3). The ‘353 art also suggests production of optical and geometrical isomers for highly related thiocillins (see e.g. p.13-14).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the micrococcin P2 of Bycroft or Acker by introducing isomers at stereochemical centers, and in doing so arrive at Chemical Formula 2. The rationale comes from ‘353 suggesting that isomers be produced of highly related thiocillins, which would have been readily applicable to Bycroft and Acker since both are directed to thiocillin species. There would have been a reasonable expectation of success because production of stereochemical isomers for a macrocyclic peptide was known in the art. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
2. Claims 6 and 7are rejected under 35 U.S.C. 103 as being unpatentable over Bycroft B and Gowland M (J.C.S. Chem. Comm. 1978, 257-258, published 1978) OR Acker et al. (J. Am. Chem. Soc. 131:17563-17565, published 2009) as applied to claims 1, 8, and 18 above, and further in view of TW201607534A (published 1 March 2016, hereafter referred to as ‘534).
The relevance of Bycroft and Acker is set forth above. The difference between the prior art references and the claimed invention is that neither discloses a secondary antibiotic.
The ‘534 art discloses administration of a thiocillin coccitomycin P1 to treat a Clostridium infection (see e.g. claim 1). ‘534 further discloses inclusion of a secondary agent, including an antibiotic such as levofloxacin, moxifloxacin, oflaoxacin, linezolid, amoxicillin, and clarithromycin (see e.g. 5th paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the compositions of Bycroft or Acker by including a secondary antibiotic as suggested by ‘534. The rationale comes both from ‘534 indicating the utility of a secondary agent with a similar thiocillin, as well as the knowledge in the art that combinations of antibiotics are often more efficacious than either antibiotic alone. There would have been a reasonable expectation of success because the skilled artisan merely had to add a second antibiotic to the micrococcin P2 composition. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 12, ‘534 also indicates the utility of vancomycin, metronidazole, and fidaxomicin in C. difficile infections (see e.g. 3rd paragraph).
3. Claims 14 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Bycroft B and Gowland M (J.C.S. Chem. Comm. 1978, 257-258, published 1978) OR Acker et al. (J. Am. Chem. Soc. 131:17563-17565, published 2009) as applied to claims 1 and 18 above, and further in view of Chan D and Burrows L (BioRxiv, doi: https//doi.org/10.1101/2020.04.23.057471, published 15 May 2020, hereafter referred to as Chan).
The relevance of Bycroft and Acker are set forth above. The difference between Bycroft and Acker is that neither discloses the claimed level of micrococcin compound.
Chan discloses thiopeptides investigated for synergy with deferasirox for inhibition of P. aeruginosa and A. baumannii growth, including micrococcin (see e.g. Figure 1). Chan discloses that all thiopeptides were prepared at 1-20 mg/ml (see e.g. Methods).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the micrococcin of Bycroft or Acker could have been prepared as the micrococcin of Chan at 1-20 mg/ml. The rationale comes from the overlapping subject matter in all three references concerning thiopeptides, as well as Chan disclosing the highly similar micrococcin P1. There would have been a reasonable expectation of success because the skilled artisan is only preparing the composition at a particular wt%, which is offered by the Chan art. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658
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