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 .
2. Claims 1-20 are under examination and are the subject of this office action.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on May 15, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Claim Rejections - 35 USC § 112(a)
4. 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.
5. Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of potentiating the activity of aztreonam (Table 1) tigemonam (Table 2), biapenem (Table 3), and meropenem (Table 4) for inhibiting the growth of certain bacterial strains overexpressing class A, class B, class C, and/or class D b-lactamases, in particular Acinetobacter baumannii, comprising administering a compound species selected from Compound 1-Compound 17, is not considered enabled for a method of treating the full scope of bacterial infections embraced by the claims, comprising administering all of the other compound species presently encompassed by Formula (I) and Formula (II). 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.
6. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
7. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to a method of treating a bacterial infection comprising administering to a subject in need thereof, one or more boronic acid compound(s) according to the structure of Formula (I), the structure of Formula (II), or a pharmaceutically acceptable salt thereof, which are alleged by the Specification to have -lactamase inhibitory activity.
8. The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
9. As discussed above, the instantly claimed invention pertains to method of treating any bacterial infection comprising administering to a subject in need thereof, one or more compound(s) of Formula (I) or Formula (II), which are alleged by the Specification to have -lactamase inhibitory activity. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
10. As to the treatment of bacterial infections, the state of the art is that “bacterial infection,” without limitation, embraces an extremely wide spectrum of infections caused by bacterial growth or poisons (toxins), such as food poisoning (gastroenteritis); some skin (cellulitis, boils, or impetigo), ear or sinus infections (pneumococcal disease); sexually transmitted infections (STIs) (e.g., chlamydia); Bacterial pneumonia; most urinary tract infections (e.g., E. coli); Lyme disease; and intestinal infections (C. diff); more specifically, infections caused by bacterial organisms including gram-positive bacteria, gram-negative bacteria, and aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, and other organisms. Most bacterial infections are treated by administering an antibiotic, however antibiotics are designed to have clinically useful activity against a few types of bacteria by targeting specific pathways (see Singh et al. 2017, Table 1 at page 65). While some antibiotics have a broader spectrum of activity than others, their activity is still limited to certain bacterial strains and no single antibiotic or b-lactamase inhibitor is effective against all types and kinds of bacterial infections in a subject, i.e., no antibiotic exists that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host (Singh et al., abstract).
11. Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods.
12. The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case of -lactamase inhibitors which, as disclosed by Drawz and Bonomo (Clin Microbiol Rev 2010, cited on Applicant’s IDS of May 15, 2024), demonstrate significantly altered activity following minor modifications, i.e.:
“The efficacy of the mechanism-based inhibitors can vary within and between the classes of-lactamases (Table 2). For class A, SHV-1 is more resistant to inactivation by sulbactam than TEM-1 but more susceptible to inactivation by clavulanate (328). Comparative studies of TEM-and SHV-derived enzymes, including ESBLs, found that the IC50s for clavulanate were 60- and 580- fold lower than those for sulbactam against TEM-1 and SHV-1, respectively (328). In our opinion, the explanations for these differences in inactivation chemistry are likely subtle, yet highly important, differences in the enzyme active sites,”
(page 169, right column, last paragraph).
13. And, the treatment of bacterial infections with antibiotics has become less predictable with the development of bacterial resistance, resulting in limited treatment options:
“Antibiotics… have a relatively short useful lifespan due to acquired resistance [6]. So a specific ideal antibiotic will always be transitory and will have to be replaced by newer ones when older ones become ineffective. Drug discovery teams almost always want to develop an ideal antibiotic but invariably hit a variety of roadblocks, mostly scientific, which they cannot overcome, resulting in development of imperfect but generally safe antibiotic.… Resistance mechanisms can include modification of the target to alter drug-binding, production of alternate mechanisms to perform the function of the target, inactivation of the drug, reduction of drug entry and expression of efflux pumps to eliminate drugs from inside bacterial cells [8]. In certain cases bacteria are not only resistant to one class of antibiotics but to several classes simultaneously, significantly limiting treatment options.”
(Singh et al., page 64, left column, third and fourth paragraphs).
14. The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification discloses the -lactamase inhibitory activity of just 17 compound species encompassed by Formula (I), wherein said Compounds 1-17 potentiate the activity of aztreonam (Table 1), tigemonam (Table 2), biapenem (Table 3), and meropenem (Table 4), for inhibiting the growth of certain bacterial strains overexpressing class A, class B, class C, and/or class D b-lactamases in vitro, (see Examples 17-20, pages 79-83). The specification fails to teach the antibacterial activity of any compound species comprising heterocyclyl or heteroaryl rings in the Markush moieties G, M, R5, R6, or R7, and does not teach the activity of any compound species of Formula (II). The Specification demonstrates the in vitro activity of Compounds 1-17 against only one type of bacterial infection, Acinetobacter baumannii (Example 20), but fails to disclose the administration of any compound(s) of Formula (I) or (II) for the treatment of any bacterial infection in a subject in need thereof.
15. Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). The Federal Circuit has repeatedly held that “the specification 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 (Fed. Cir. 1993) (emphasis added).
16. At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
17. As to the first inquiry, as discussed above, the claims are drawn to a method of treating a bacterial infection comprising administering to a subject in need thereof one or more compounds of Formula (I) and/or Formula (II), which are alleged by the Specification to act as -lactamase inhibitors. Considering that Formulae (I) and (II) each encompass hundreds of millions of compound species, and potentially billions of compound species, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses only 17 compound species encompassed by Formula (I) as recited by the claims, and fails to disclose any compound species comprising heterocyclyl or heteroaryl rings.
18. Regarding bacterial infections, the Specification provides a non-limiting list of examples of bacterial infections including Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus (See paragraph [0166]).
As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
19. Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to a method of treating any bacterial infection, without limitation, comprising administering to a subject in need thereof one or more compounds of Formula (I) and/or Formula (II). Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formulae (I) and (II) with respect to the disclosure, because Formulae (I) and (II) each encompass hundreds of millions of compound species, and potentially billions of compound species, whereas the instant Specification demonstrates only 17 such compound species of Formula (I) exerting antibacterial activity, and fails to disclose the activity of any compound(s) of Formula (II). Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by Formulae (I) and (II) would exert the alleged activity for treating the vast scope of bacterial infections embraced by the claims, based on the limited disclosure of 17 active compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Thus, in order to identify usable compounds of Formula (I) and/or Formula (II), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 17 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (I) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays” (Anderson, Page 794, Column 1) and “hit rates are on the order of one in ten” (Thiel, Page 517, Column 2). The Specification fails to disclose any compounds of Formula (II) that would be usable as a starting point. Given the unpredictability of -lactamase inhibitors discussed by Drawz and Bonomo, it is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) (i.e., those not identified by rational drug design based on the instant disclosure), let alone compounds of Formula (II) would be effective against the full scope of bacterial infections embraced the claims is even less predictable. As such, the only way to ascertain which of the hundreds of millions, and potentially billions, of claimed compounds encompassed by Formula (I) and Formula (II) are usable based on the limited disclosure would require undue experimentation.
20. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Claim Rejections - 35 USC § 112(b)
21. 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.
22. Claim 14 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.
Claim 14 is unclear in the following aspects:
(a) In the present instance, claim 14 recites “Ampicillin” in line 2, followed by the recitation of “Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin” in parentheses, which is confusing because it is not clear if Applicant is further claiming the compounds listed in the parenthetical as examples of ampicillin, or if Applicant is further defining ampicillin as these compounds. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by the parenthetical is (a) merely exemplary, and therefore not required, or (b) a required feature of the claims.
(b) Likewise, in line 3, claim 14 recites “Carbenicillin”, followed by the recitation of “Carindacillin” in parentheses, which is which is confusing because it is not clear if Applicant is further claiming the compound listed in the parenthetical as examplary of carbenicillin, or if Applicant is further defining carbenicillin as this compound.
(c) In line 4, claim 14 recites “Mecillinam”, followed by the recitation of “Pivmecillinam” in parentheses, which is confusing because it is not clear if Applicant is further claiming the compound listed in the parenthetical as examplary of mecillinam, or if Applicant is further defining mecillinam as this compound.
(d) In line 5, claim 14 recites “Benzylpenicillin”, followed by the recitation of “G” in parentheses, which is confusing and extraneous, since Benzylpenicillin is also known as Penicillin G. Therefore the parenthetical “(G)” is not necessary.
(e) In line 6, claim 14 recites “Phenoxymethylpenicillin”, followed by the recitation of “V” in parentheses, which is confusing and extraneous, since Phenoxymethylpenicillin is also known as Penicillin V. Therefore the parenthetical “(V)” is not necessary.
(f) In line 7, claim 14 recites “Cloxacillin”, followed by the recitation of “Dicloxacillin, Flucloxacillin” in parentheses, which is confusing because it is not clear if Applicant is further claiming the compounds listed in the parenthetical as examples of cloxacillin, or if Applicant is further defining cloxacillin as these compounds.
Claim Rejections - 35 USC § 103
23. 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.
24. 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.
25. 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.
26. Claims 1, 2, 4 and 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Reddy et al., WO 2016/149393 A1 (published September 22, 2016).
Claim 1 is drawn to a method of treating a bacterial infection in a mammal (more specifically, a human (claims 17-18), comprising administering to a (human) subject in need thereof, one or more compounds according to Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in particular the following compound species:
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(claim 4), which is also embraced by claim 2.
27. Reddy et al. teach a method of treating a bacterial infection in a human subject (paragraph [0193]), comprising administering to said human a compound according to the genus of functionally related boronic acid derivatives having the same core structure that is instantly recited by Applicant (page 15, Formulae (I’) or (II’)) and specifically disclose the species:
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(paragraph [0015]), which differs from Applicant’s compound of claim 4 solely in the position of the hydroxyethyl substituent on the benzoxaborinine ring.
28. As such, the genus of compounds disclosed by Reddy et al. fully encompasses the compounds of the instant invention and also demonstrates beta-lactamase inhibitory activity for treating bacterial infections, but Reddy et al. do not teach the administration of a single disclosed compound or species that anticipates the instant claims.
29. Yet, compounds that are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious). Regarding the stereoisomerism of the compound of Reddy et al., see Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). See MPEP 2144.09.
30. Furthermore, Reddy et al. generically indicate that the “Y2-G” substitution can be in the meta-position relative to the “-OH” substituent on the benzoxaborinine ring, e.g., see compounds according to Formula Ib:
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(paragraph [0025]).
31. Regarding the comprehensive of the genus disclosed by Reddy et al., a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").
32. Additionally, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
33. Therefore, one of skill in the art before the effective filing date of the claimed invention would have been motivated to substitute Applicant’s claimed compound
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for the compound taught by Reddy et al:
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, for administration to a human subject in need thereof to treat a bacterial infection, and would have had a reasonable expectation of success. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to substitute the meta-isomer for the ortho-isomer taught by Reddy et al. because compounds that are similar in structure (e.g., position isomers) are expected to behave similarly.
As such, claims 1, 2, 4, 17 and 18 are prima facie obvious.
Claim 11 is drawn to claim 1, further comprising an additional medicament selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent (claim 12), in particular a b- lactam antibacterial agent (claim 13), selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam (claims 15 and 16).
34. Reddy et al. additionally teach co-administering the boronic acid derivative with an additional medicament (paragraphs [0195]-[0198]), specifically naming Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, Panipenem, Aztreonam, Tigemonam, and Carumonam as a preferred medicaments (paragraphs [0199]-[0200]).
35. Thus, one skilled in the art before the effective filing date of the claimed invention would have been motivated to co-administer the boronic acid compound:
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with an additional medicament having antimicrobial activity in order to achieve an additive effect in the treatment of bacterial infection in a human subject in need thereof. It would have been obvious to one of skill in the art to combine the above boronic acid compound with an additional antimicrobial compound specifically named by Reddy et al., with a reasonable expectation of success.
As such, claims 11-16 are prima facie obvious.
Claim 19 is drawn to claim 1 and limits the bacterial infection to a bacteria selected from the group consisting of Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus. Claim 20 is drawn to claim 1, and limits the bacterial infection to a bacteria selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.
36. Reddy et al. additionally teach examples of bacterial infections to be treated including:
“gram-positive bacteria, gram- negative bacteria, aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.
More examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus,” (Reddy et al. paragraphs [0204]-90205]), which encompass the bacterial infections recited in claims 19 and 20.
37. Therefore, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat any of the above-named bacterial infections specifically named by Reddy et al., comprising administering the above boronic acid compound to a human subject in need thereof. One skilled in the art would have been motivated before the effective filing date of the claimed invention to administer said boronic acid derivative to treat a bacterial infection disclosed by Reddy et al., with a reasonable expectation of success.
As such, claims 19 and 20 are prima facie obvious.
Double Patenting
38. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
39. A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
40. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
41. Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23 of U.S. Patent No. 9,132,140 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 is directed to a method of treating a bacterial infection, comprising administering to a subject in need thereof a compound of Formula (I) or Formula (II),
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or a pharmaceutically acceptable salt thereof, more specifically wherein the subject is a mammal that is a human (claims 17 and 18). Claims 2-10 are drawn to claim 1, and further limit the compound species of Formula (I) or Formula (II). Claim 11 is drawn to the method of claim 1, further comprising administering an additional medicament (wherein the additional medicament is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent (claim 12), more specifically, a b-lactam antibacterial agent (claim 13)).
Claim 14 is drawn to claim 13, claim 13, wherein the β-lactam antibacterial agent is selected from the group consisting of Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA- 101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442. Claim 15 is drawn to claim 13, wherein the β-lactam antibacterial agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, and Panipenem or selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam (claim 16)). Claim 19 is drawn to claim 1, and further limits the bacterial infection to be treated to Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus. Claim 20 is drawn to claim 1, and further limits the bacterial infection to be treated to Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.
42. Claim 21 of U.S. 9,132,140 B2 recites a method of treating a bacterial infection, comprising administering a boronic acid derivative of Formula (I-1) or Formula (I-2) (recited in Claim 1):
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wherein “n”=0; and the other variables are as defined in the claims, which are positional isomers of Applicant’s recited species of claims 2-10. Claim 22 is drawn to Claim 21 and recites co-administering the pharmaceutical composition with an additional medicament wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent. Claim 23 is drawn to Claim 21 and recites wherein the additional medicament is a b-lactam antibacterial agent, and wherein the b-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
43. Thus, the genus of compounds recited in U.S. 9,132,140 B2 of Formula (I-I) is fully embraced by and only differs from Applicant’s instant genus of Formula (I) as positional isomers, i.e. the “Y-(CR8R9)n-G” substituent is in the ortho position relative to the -OH moiety , wherein Applicant’s “-CH2-G” substituent is in the meta position relative to the -OH moiety. The genus of compounds recited in U.S. 9,132,140 B2 of Formula (I-2) is fully embraced by the genus that is instantly recited by Applicant in Formula (II) but differs in the placement of the “G” substituent on the ethyl group, i.e., the “Y-(CR8R9)n-G” substituent is in the “2” position relative to the ring , wherein Applicant’s “-CH2-G” substituent is in the “1” position relative to the ring.
44. Yet, compounds that are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
45. Therefore one skilled in the art would be motivated to treat the instantly recited bacterial infections comprising administering the instantly recited positional isomers of the boronic acid derivatives previously recited in U.S. 9,132,140 B2, and would have had reasonable expectation of success that the similar compounds would have similar pharmacokinetic properties, oral availability, antimicrobial potency, and/or duration of effect, etc.
46. And, "[a]n obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990). See MPEP § 2144 for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds.
47. Regarding the comprehensive of the genus recited, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Bio