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
The amendment to the claims filed after non-final office action on November 28, 2025 is acknowledged. Claim 21 was amended, claims 1-20 were canceled, claims 41-42 were newly added and claims 21-42 are pending in the instant application. The restriction was deemed proper and made final previous office action.
The restriction was deemed proper and made FINAL in the previous office action. Claims 31, 34 remain withdrawn due to being drawn to a non-elected invention species. Claims 21-30, 32-33, 35-42 are examined on the merits of this office action.
Withdrawn Rejections/Objections
The rejection of claims 39-40 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claims 39-40 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-22, 28, 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Poulsen (WO8802600 A1) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-24, 35, 37-40 under 35 U.S.C. 103 as being unpatentable over Deaton (US20130101634, cited in Applicant’s IDS) in view of Nagaoka (Letters in Applied Microbiology51, 546–551, 2010, cited in Applicant’s IDS), Mason (US20170165208, cited in Applicants IDS) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-24, 28, 35-36 under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-24, 26, 28, 35-36 under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) as applied to claims 21-24, 28, 35-36, in further view of Fatima (J Pak Med Assoc, Vol. 66, No. 8, August 2016, pages 1019-1023) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-24, 27, 28, 35-36 under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) as applied to claims 21-24, 28, 35-36, in further view of Meisel (J Dent Res 005 Oct;84(10):937-41. and Turck (EFSA Journal 2018;16(12):5484, www.efsa.europa.eu/efsajournal) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-24, 28-30, 32-33, 35-36 under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) as applied to claims 21-24, 28, 35-36, in further view of Friedman (Therapeutic Mouthwash for Preventive and Post-Surgery Care, https://bestlincroftdentist.com/blog/therapeutic-mouthwash-preventive-post-surgery-care/, 2016) is withdrawn in view of amendment of the filed November 28, 2025.
The rejection of claim(s) 21-25, 28, 35-36 under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) as applied to claims 21-24, 28, 35-36, in further view of Onishi (Archives of Oral Biology, Volume 53, Issue 3, March 2008, Pages 257-260) is withdrawn in view of amendment of the filed November 28, 2025.
Maintained/Revised Objection-Specification and Drawings
The specification and drawings are objected to under 37 CFR 1.71 because the terms LYSIBIOTIC™ and LYSODENT™ are improperly identified as trademarks. A search of USPTO records fail to revel any registered marks for these terms in the relevant field of endeavor. Applicant is required to either provide evidence of trademark status (and then include generic terminology) or amend the specification to remove the trademark designations and replace with appropriate generic terminology (see MPEP 608.01(v)).
The amendment filed November 28, 2025 is objected to under 35 U.S.C. 132 (a) because it introduces new matter into the disclosure. The added material which is not supported by the original disclosure is as follows: Lysibiotic (lysozyme preparation). Applicant is require to cancel the new matter in the reply to this office action.
Maintained/Revised Rejections
Claim Rejections – 35 USC § 112, first paragraph
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 21-30, 32-33, 35-42 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 treating of specific bacterial disorders like gum disease comprising administering lysozyme containing compositions, does not reasonably provide enablement for treatment of or preventing any bacterial infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The claims are drawn to “A method of treating or preventing a bacterial infection in a mammal, comprising: administering to the oral cavity of the mammal a pharmaceutical composition consisting of: i. about 2% by weight to about 80% by weight of lysozyme, ii. about 2% by weight to about 40% by weight of a pharmaceutically acceptable chelating agent, iii. about 0.7% by weight to about 20% by weight of a pharmaceutically acceptable pH stabilizing salt, wherein the pH stabilizing salt has buffering capacity in the range of pH 3.0 to pH 7.0” (see claim 21). *Please note that the patient population is not required to have a bacterial infection as the term prevention encompasses patients that do not have bacterial infections. Thus, the claims encompass treating or preventing any bacterial infection in any patient population via oral administration.
Furthermore, claim 21 was amended to include “consisting” language. Claim 36 recites “wherein the pharmaceutical formulation is in form of a chewable tablet”. However, chewable tablets typically require additional formulation components such as binders, fillers, sweeteners, lubricants or other excipients to provide appropriate compressibility, palatability, and structural integrity. The use of the transitional phrase “consisting of” excludes the presence of additional components beyond those expressly recited in the claims. The specification does not describe how a chewable tablet could be formulated using only the recited ingredients without the inclusion of additional excipients commonly required for tablet manufacture. As such, a person of ordinary skill in the art would not reasonably be able to prepare a chewable table consisting solely of the recited components without undue experimentation. Accordingly, the specification does not enable the full scope of the claimed invention.
The breadth of the claims
The claims are broad with respect to the patient population being treated. Applicant’s specification fails to adequately describe prevention of bacterial infection or treating/preventing bacterial infection in patients broadly. Applicant’s specification states “ In some aspects of the invention, the pharmaceutical formulation of the present invention may be used to treat bacterial infections of the skin. For example, the pharmaceutical formulation may be used to treat or prevent infections in skin sores persistent in diabetic and immunologically debilitated patients; skin burns (at different levels) which often become infected because of the exposure to the environment and cause the patient to undergo a painful recovery procedure and other bacterial skin infections.
In an aspect of the invention, the pharmaceutical formulation disclosed herein may be used to treat bacterial infections of the oropharyngeal, pylorus and esophageal tissue areas. Permanent incubation regions for bacteria lie in the sinuses, oral cavity (e.g., the gums) and in the throat, causing persistent infection in the mucosal tissue surrounding these regions. Since these areas have a common port of entry, the pharmaceutical formulation of the present invention allows cotemporaneous treatment of these areas.
In some embodiments the pharmaceutical formulation may be used to treat bacterial infections of the large intestine, including acute Salmonellosis, Colitis and Diverticulitis. In some embodiments the main component of the formulation is lysozyme present in sufficient quantity, and administered in a high volume carrier (such as water), that a pharmaceutically effective amount of enzyme is provided the large intestine. In non-limiting embodiments the formulation includes an agent that induces intestinal flushing promoting the flow of water into the large intestine forcing the bacteria into the liquid suspension that forms immediately in the intestine cavity. This allows lysozyme to easily attack and destroy the bacteria (a purgative effect).
In certain embodiments the pharmaceutical formulation may be used to treat bacterial infections present in the upper and lower respiratory tissues, including the sinuses and lungs. These two regions have a common port of entry, but at the same time often sinuses become incubation zones that allow for reinfection. In another aspect of the invention the pharmaceutical formulation provided herein may be used to treat or cure bacterial infections in the blood stream or vital organs of a mammal. Sinus, lungs, blood and the vital inner organs are very delicate and sensitive to any non-soluble materials. Thus, some aspects of the present invention provide formulations containing only lysozyme and ethylenediaminetetraacetic acid (EDTA). In some embodiments sodium bicarbonate is provided with EDTA in acid form. In yet other embodiments, the pharmaceutical formulation includes EDTA salt and minute amounts of sodium bicarbonate to stabilize the pH of the formulation after it is dissolved in an aqueous solution” (see paragraphs 0021-0023). Applicant’s specification states “The inventors of the present disclosure have demonstrated surprisingly that a pharmaceutical formulation comprising lysozyme as provided herein acts as a universal bactericide, killing both Gram negative and Gram positive bacteria. The pharmaceutical formulation of the present disclosure does not produce harmful side effects on human tissue and organs, even during prolonged use” (see paragraph 0054)
Different bacteria (i.e. different bacteria (gram positive, gram negative, antibiotic resistant) have very different methods of pathogenesis and are treated very differently.
Applicants have not shown treatment/prevention of bacterial infections broadly in patients.
The State of the Prior Art
The state of the art is relatively low with regards to use of lysozyme, chelating agent and salt for treating/preventing bacterial infections broadly in any patient that has any type of infection.
In general, treatment of bacterial infections including gram-positive and negative bacteria is highly unpredictable given differences of the bacteria structurally and in the mechanisms of pathogenesis. Opal (Ovid, Critical Care Medicine, Issue: Volume 27 (8), 1999, pages 1608-1616, cited in IDS) teaches a fundamental difference between Gram-positive and Gram-negative bacteria is the way in which they initiate disease. Gram-positive bacteria depend on the production of powerful exotoxins (e.g., tetanus, botulism, diphtheria); with Gram-negative bacteria, it is principally the cell wall component, endotoxin that is implicated in pathogenesis. Gram-positive sepsis differs from Gram-negative sepsis in that the organisms often arise from skin, wounds, soft-tissue structures, and catheter sites rather than enteric or genitourinary sources. Additionally, Gram-positive organisms require a highly orchestrated host response, with intracellular killing by neutrophils and macrophages. This is often not the case for Gram-negative pathogens, which may be readily killed in the extracellular space by antibody and complement.
In Gram-negative bacteria, an inner lipid plasma bilayer is covered with a thin layer of peptidoglycan. Overlying this is an outer membrane, in the outer part of which is endotoxin. There is compelling evidence that endotoxin plays a key role in the pathogenesis of Gram-negative infection. Most of the toxicity of endotoxin resides in the innermost core region, which consists of lipid A. Endotoxin can be found in the blood of patients with Gram-negative sepsis.
Taken together, these and other data provide persuasive evidence that endotoxin is the principal component of Gram-negative bacteria responsible for initiating the process of sepsis. Nevertheless, it must be acknowledged that endotoxemia cannot be demonstrated in all cases of Gram-negative sepsis and that endotoxemia and bacteremia are not necessarily synonymous (see pages 3-4, The Immunopathogenesis of Gram-positive Sepsis, paragraphs 1-4).
Endotoxin is not present in Gram-positive bacteria. Instead, the cell wall contains a thick (20-80 nm) layer of peptidoglycan, which lies directly over the plasma membrane. Embedded in the peptidoglycan are molecules of lipoteichoic acid. Several in vitro studies have demonstrated that these structural components of Gram-positive cell walls are able to mimic some of the properties of endotoxin, for example, in their ability to induce proinflammatory cytokines from mononuclear cells. Furthermore, data from work with S. aureus suggest that there is a complex synergistic relation between peptidoglycan and lipoteichoic acid in their ability to cause shock; some have even advanced toward identifying the precise structural components of the molecules responsible for this effect. What is not clear is whether these processes are of clinical significance; there is no doubt that peptidoglycan is considerably less potent than endotoxin, and it is not known whether the amounts of these Gram-positive cell wall components that are present during infection (locally or systemically) are sufficient to reproduce the effects seen in vitro (see page 4, second paragraph).
The production of soluble extracellular toxins is one of the hallmarks of disease caused by Gram-positive bacteria. The list is extensive, but examples include the toxins of clostridial species (gas gangrene, antibiotic-associated colitis); diphtheria (Corynebacterium diphtheriae); food poisoning (Bacillus cereus, S. aureus); and anthrax (Bacillus anthracis). The mode of action of many of these toxins is highly specific. For the Gram-positive bacteria associated with septic shock, however, toxins of a different kind seem to be involved.
In septic shock, the clearest associations are with staphylococcal infection and with streptococcal shock syndrome caused by Streptococcus pyogenes. The working hypothesis is that infection leads to local or systemic release of toxins, massive lymphocyte activation, and release of T-cell cytokines, resulting in cellular injury and organ failure. Attempts to modulate T-cell activation in experimental models of superantigen-induced injury with glucocorticoids, cyclosporine A, interleukin (IL)-2 deletion, or antibodies directed against cytokines or superantigens have generally proved to be beneficial. The value of this type of intervention in human diseases from superantigen-mediated immune activation is not known but is a promising area for further clinical research (see page 4, paragraphs 3-6).
In summary, although the notion that Gram-negative bacteria cause shock by their endotoxin, whereas shock caused by Gram-positive bacteria is produced by exotoxins, has been shown to be over simplistic, it is clear that there are fundamental differences in the ways in which these two groups of organisms assault the immune system. Therapeutic strategies designed to alter the host response to bacterial sepsis may need to explain these basic differences in the pathophysiology of septic shock caused by Gram-positive or Gram-negative organisms (see page 5, paragraphs 2-5).
The complexities of host-pathogen interactions to a wide variety of potential human pathogens make it likely that response to therapeutic agents that affect the immune response varies substantially from patient to patient. A multitude of variables may interact to determine the responsiveness to anti-inflammatory agents in sepsis. Among those variables may be the nature of the infecting organism.
Gram-positive organisms lack endotoxin but possess an array of potential virulence factors that contribute to their ability to evade host defenses and to disseminate in the systemic circulation. Antiphagocytic capsules and outer membrane proteins, various exotoxins, lipoteichoic acid, intrinsic resistance to extracellular bacteriolysis, and invasive properties of many Gram-positive pathogens necessitate a coordinated host response for effective microbe clearance. The relative importance of the proinflammatory cytokine response by the host innate immune response in clearance of microorganisms may differ between microbic pathogens. This may alter the risk-benefit relation of anti-inflammatory agents in the treatment of Gram-positive vs. Gram-negative pathogens. Results of several clinical trials with anti-inflammatory drugs for sepsis indicate that responsiveness may differ, depending on the causative bacterial pathogen or pathogens.
Furthermore, treatment of sepsis still remains a serious concern and challenge in hospitals. Bacterial toxins from both gram-positive and gram-negative bacteria allow the pathogen to modulate host defenses through their interaction with cells enabling the bacteria to escape the innate immune system to remote organs. The type of toxin plays a major role in the outcome of disease (see page 8, paragraphs 2-6).
Thus, based on the prior art, it is clear that the mechanisms of action of between gram-negative and gram-positive species, and even within each species, differs greatly and often requires different modes of treatment and or prevention. This further contributes to the unpredictability of treating/preventing any bacteria in patient population with any type of infection.
The Predictability or Unpredictability of the Art/ The Relative Skill of Those in the Art
The prior art pertaining to preventing bacterial infections in any patient population with an “infected area” is highly unpredictable given that the mechanisms of action of between gram-negative bacteria, gram-positive bacteria and differing fungi and protists (different infective agents), differs greatly and often requires different modes of treatment (see discussion of the prior art, supra). There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). Where the predictability in the art is low, Applicant is required to provide greater disclosure and guidance to comply with the enablement requirement. MPEP § 2164.03.
It is not within the skill of the ordinary artisan to prevent bacterial infection with the compositions of the instant claims.
Amount of Guidance/The Presence or Absence of Working Examples
In the instant case, applicants reduced to practice the following: Figures 1-15 and use of Lysodent™ for treatment of patients undergoing dental surgery and evaluation of gingival index. The Lysodent formulation is found in Table 1 which falls within the scope of instant claim 21. However, there is no examples of prevention or treatment of bacterial infections in any patients. The Applicant further states “The inventors of the present disclosure have demonstrated surprisingly that a pharmaceutical formulation comprising lysozyme as provided herein acts as a universal bactericide, killing both Gram negative and Gram positive bacteria. The pharmaceutical formulation of the present disclosure does not produce harmful side effects on human tissue and organs, even during prolonged use” (See paragraph 0161, Example 2). However, no wherein the specification or in the art is the term “Lysibiotic” described. It is unclear what formulation is encompassed by “lysbiotic” which contributes to the unpredictability of determining enablement for the present invention. The term Lysodent™ is sufficiently described (see paragraph 0129-0130).
The specification does not disclose sufficient examples of treatment of or prevention of bacterial infections in any patient population other than as a dental product (which is not representative of the claims as a whole). Given the breadth of the genus (see above discussion) and the unpredictability of the prior art (see above discussion), use of Lysodent for treatment of oral complications is not sufficient for enablement of the entire claim genus (treating/preventing any bacterial infection.
Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if compounds of the instant invention would be effective at treating/preventing any bacterial infection in any patient. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Response to Applicant’s Arguments
Applicant submits that the mechanism of action of the claimed invention is inherently broad-spectrum. Indeed the claimed composition is not a specific drug targeting a specific bacterial enzyme; it is a universal bactericidal system. The claimed compositions target the most basic structures of bacterial cells: the cell wall and the outer membrane, and therefore the composition is effective against both Gram-positive and Gram-negative bacteria, as shown in our the data in the specification. The Surgical Study is proof of concept. Demonstrating efficacy in a post-surgical oral environment a challenging scenario and thus a person of ordinary skill in the art would understand that the composition would work against the same bacteria in other parts of the body, or against other bacteria susceptible to the same physical lysis mechanism. The clinical studies for dental surgery and gingivitis are not narrow examples; they are a severe test of the invention's efficacy. Because the oral cavity is a complex, diverse microbial environment a person of ordinary skill in the art would understand that successfully preventing and treating infection in this context, especially in the highly susceptible post-surgical wound, would mean that the composition is effective against a broad range of bacteria. The claimed composition functions through a dual physical assault on the most conserved and essential structures of bacterial cells:
" Lysozyme Activity: This enzyme catalyzes the hydrolysis of 1,4-beta-linkages between N- acetylmuramic acid and N-acetyl-D-glucosamine residues in the peptidoglycan polymer. This peptidoglycan layer is a universal and critical component of the cell wall in virtually all Gram-positive bacteria. Furthermore, by compromising the overall structural integrity of a bacterial cell, it also sensitizes and synergizes with agents that target Gram-negative bacteria. " Chelating Agent Activity (e.g., EDTA): The primary mechanism against Gram-negative bacteria involves the chelation of divalent cations, specifically magnesium (Mgr+) and calcium (Cap+). These ions are critical for stabilizing the outer membrane lipopolysaccharide (LPS) layer. Their removal by a chelator causes disorganization and increased permeability of this protective barrier, leading to cell lysis and enhanced susceptibility to lysozyme. This combination constitutes a broad-spectrum, mechanistic attack on fundamental bacterial structural integrity, not a narrow, metabolic inhibition. A person skilled in the art, upon reviewing the specification and understanding this mode of action, would logically conclude that its application is not limited to the oral cavity but extends to bacterial infections in general, provided the formulation can be delivered to the site. The specification provides the "recipe" and the fundamental scientific principle. A skilled scientist or formulator would not need to invent anything new to apply this known composition to a new location; they would only need to follow standard pharmaceutical development practices for different delivery routes (e.g., cream vs. mouthwash), which is routine and does not constitute "undue experimentation."
Applicants arguments have been fully considered but not found persuasive. Applicant argues that the claimed composition operates through a broad spectrum mechanism of action, asserting that the composition targets fundamental bacterial structures such as the cell wall and outer membrane, thereby making the composition effective against both gram positive and gram negative bacteria. Applicant’s arguments have been fully considered but not found persuasive. A proposed scientific explanation or mechanism of action does not, by itself, establish enablement of the full scope of the claim invention. The claims encompass treating or preventing any bacterial infection in a mammal, while the specification provides only limited examples relating to dental procedures and gingival infections. The specification does not provide sufficient guidance or representative examples demonstrating tha the claimed composition would be effective for treating/preventing bacterial infections broadly across different tissues, infection types or patient populations.
Applicant further argues that the dental surgery and gingivitis studies disclosed in the specification represent a challenging microbial environment and therefore demonstrate that the composition would be effective against a broad range of bacteria. Applicant’s argument is not found persuasive. While the oral cavity may contain a diverse microbial population, the examples provided in the specification relate only to localized oral infections associated with dental procedures. These examples do not reasonably represent the full scope of the claims, which encompass treating or preventing bacterial infections general in a mammal, including infections in other tissues or organs. The specification does not provide representative examples or sufficient guidance demonstrating that the claimed formulation would be effective in treating bacteria infections outside the oral environment.
Applicant further argues that a person of ordinary skill in the art would recognized that the composition could be applied to infections in other parts of the body and that adapting the formulation for different delivery routes would involve only routine pharmaceutical formulation techniques. Applicant’s arguments are not found persuasive. The claims specifically recite administering the pharmaceutical composition to the oral cavity of a mammal. The specification provides no teaching or evidence demonstrating that administration to the oral cavity would effectively treat bacterial infections located elsewhere in the body, such as infections in internal organs, systemic infections or infections located in tissues remote from the oral cavity. The absence of such guidance indicates that a person of ordinary skill in the art would be required to perform undue experimentation to determine whether the claimed method would be effective across the full scope of bacterial infections encompassed by the claims.
Applicant argues that the specification provides the necessary “recipe” and scientific principles for applying the formulation to different infection sites. Applicant’s arguments are not found persuasive. While the specification may disclose the general composition of the formulation, enablement requires that the specification teach those skilled in the art how to make and use the invention across the full scope of the claimed invention without undue experimentation. The specification provides only limited examples relating to dental applications and does not provide sufficient direction or working example demonstrating the treatment or prevention of bacterial infections across the broad range encompassed by the claims.
For the reasons stated above, applicants arguments do not overcome the rejection under 35 U.S.C 112(a) scope of enablement.
New Rejections
Claim Rejections - 35 USC § 112
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 36, 41-42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 36 depends from claim 21, which recites a pharmaceutical formulation consisting of lysozyme, EDTA and a pharmaceutically acceptable pH stabilizing salt. The transitional phrase “consisting of” excludes additional ingredients. However, the specification describes the chewable tablet embodiment as including additional components, such as pharmaceutically acceptable resin and optional flavoring or coloring agents (see paragraph 0066). Because the chewable tablet described in the specification requires additional ingredients, it is unclear how the chewable table of claim 36 can fall within the scope of claim 21. By using the phrase “consisting of”, additional ingredients are required to make a chewable tablet. Therefore, the scope of the claim is unclear and contradictory.
Claims 41 and 42 are dependent on canceled claim 1 and thus, the metes and bounds of the claims cannot be determined. Thus, claims 41-42 are indefinite. For examination purposes, claims 41-42 will be interpreted as being dependent on claim 21.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 22, 25, 26-27, 42 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 claims “administering to the oral cavity of the mammal a pharmaceutical formulation consisting of i) about 2% by weight to about 80% by weight of lysozyme, ii). About 2% by weight to about 40% by weight EDTA, iii) about 0.7% by weight to about 20% by weight of a pharmaceutically acceptable….in the range of pH 3.0 to pH 7.0”. Claim 22 is dependent on claim 21 and claims “wherein the pharmaceutical formulation is dissolved in a pharmaceutically acceptable aqueous solution prior to administration”. However, due to the consisting language of claim 21, the formulation is closed and thus, cannot contain any additional agents including an aqueous solution and thus, claim 22 broadens the scope of instant claim 21.
Similarly, claim 25 is also dependent on claim and claims “further comprises a resin”. As stated above, due to the consisting language of claim 21, the formulation is closed and thus, cannot contain any additional agents including a resin and thus, claim 25 broadens the scope of instant claim 21.
Furthermore, claim 26 is also dependent on claim and claims “further comprises zinc oxide”. As stated above, due to the consisting language of claim 21, the formulation is closed and thus, cannot contain any additional agents including zinc oxide and thus, claim 26 broadens the scope of instant claim 21.
Furthermore, claim 27 is also dependent on claim and claims “further comprises magnesium citrate”. As stated above, due to the consisting language of claim 21, the formulation is closed and thus, cannot contain any additional agents including magnesium citrate and thus, claim 27 broadens the scope of instant claim 21.
*Please note that claim 42 is rejected under 35 U.S.C. 112(b) for being dependent on a canceled claim. However, it is being interpreted as being dependent on claim 1.
Furthermore, claim 42 is also dependent on claim 21 and claims “wherein the pharmaceutical formulation is dissolved in an aqueous solution”. As stated above, due to the consisting language of claim 21, the formulation is closed and thus, cannot contain any additional agents including aqueous solutions and thus, claim 42 broadens the scope of instant claim 21.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 21, 23-24, 28, 35-36, 41 are rejected under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1, cited previously) in view of Poulsen (WO8802600 A1, cited previously) and Boland (Journal of Food Protection, Vol. 67, No. 2, 2004, Pages 285–294).
Stein teaches a composition comprising a chelator and a base, wherein the chelator and base provide microbial affecting activity (see claims 1 and 19) and in a mammal (see claim 19). Stein teaches wherein the chelators EDTA (see claim 3) and in a concentration range of .0005-30% of the composition (see claim 5). Stein teaches wherein the base is lysozyme and/or sodium bicarbonate (see claim 7), in a concentration of 0.0001-15% of the composition (see claim 9) and wherein more than one base is used (see claim 8). Stein teaches wherein the composition is for oral care (claim 12) and in particular as a mouthwash or a tablet (see claim 14). Regarding claim 41, Stein teaches use in a mammal (Claim 19). Regarding claims 28 and 41, Stein teaches the composition is used for treating and preventing cavities and gingivitis (see claim 16). Stein teaches buffering agents (see paragraph 0052) and in particular pH-adjusting and buffering agents (see paragraph 0063, lines 1-3) but not a specific amount of pH adjusting stabilizing salt. Stein teaches at a pH of 7-8, biofilms were inhibited (see paragraph 0112). Regarding claims 35-36, Stein teaches the formulations may be in form of powder (see paragraph 0042) and chewable tablet (see paragraph 0052, 0059, rapid melt tablets). Stein therefore teaches compositions comprising EDTA and lysozyme for use in promoting oral health in the oral cavity.
Stein is silent as to the specific concentration ranges of lysozyme and EDTA (even though they overlap) recited in instant claims 21 and 23 and does not explicitly disclose the claimed range of 0.7-20% buffering salt.
Poulsen teaches oral care bactericidal compositions for applying to the oral cavity for treating and preventing gingivitis (see abstract). Poulsen further teaches the composition may be in form of a solution to be applied to spaces between teeth and gingival pockets (see page 10, lines 16-22). Regarding claim 35, Poulsen teaches the formulation in form of a powder (see page 11, lines 9-10). Regarding claim 21, Poulsen specifically teaches wherein the solution comprises 0.03 grams of lysozyme per ml (which 3%), sodium EDTA at 0.05 mmol (which is 1.86% given disodium EDTA has a molecular weight of 372.24 gm/mol) and in an aqueous buffer with 10-200 mM of Na2HPO4 at pH 6.0. Regarding the sodium phosphate pH stabilizing buffer, 10 mM Na2HPO4 is about .95%, 100 mM is 9.5% and 200 mM is 18.9% of the 1 mL solution thus meeting the limitations of instant claim 21. Regarding the percentage of EDTA, 1.86% meets the limitations of about 2% of EDTA which is being interpreted as +/- 10% without any specific guidance from the specification.
Boland teaches that EDTA enhances the antimicrobial activity of lysozyme by chelating divalent cations that stabilized bacterial cell membranes, thereby increasing bacterial susceptibility to lysozyme mediated cell wall degradation (see page 285, left column). Boland thus teaches that combining EDTA with lysozyme alone provides enhanced antibacterial activity (independent of other components).
It would have been obvious before the effective filing date of the claimed invention to formulate a composition consisting of lysozyme, EDTA and buffering salt such as Na2HPO4 as taught by Poulsen in the oral antimicrobial compositions of Stein. Stein teaches that the antimicrobial activity results from the combination of chelator such as EDTA and a base (or bases) such as lysozyme. Boland further teaches that EDTA enhances the antimicrobial activity of lysozyme by destabilizing membranes, thereby increasing susceptibility to lysozyme mediated cell wall degradation. Thus, the prior art identifies lysozyme and EDTA as the components responsible for the antibacterial activity and one of ordinary skill in the art would have been motivated to use the combination for promoting oral health including treating/preventing oral diseases associated with microbial growth such as gingivitis. Furthermore, one of ordinary skill in the art would have been motivated to do so given the amounts of each component and the stabilizing salt of Poulsen are being utilized for the same purpose, treatment/prevention of gingivitis and inhibiting detrimental pathogens involved in oral diseases such as gingivitis.
There is a reasonable expectation of success given that the amounts taught by Poulsen are effective for the same purpose of Stein. Furthermore, the amounts of each component are considered results effective variables (EDTA, Lysozyme and pH stabilizing salt). Regarding claims 21 and 23, It would have been obvious to optimize each component (within the ranges taught by the prior) to achieve optimal therapeutic activity (antibacterial activity) in treating dental disease caused by bacteria (see MPEP 2144.05 I-II).
Regarding the “consisting language” of claim 21, given that these components provide antimicrobial activity, one of ordinary skill in the art would have recognized that other optional formulation ingredients could be omitted and that a simplified formulation containing only the active antimicrobial components and a pharmaceutically acceptable buffering salt could be used. Formulating compositions with the minimum number of components necessary to achieved the desired therapeutic effect represents routine formulation optimization and would have been obvious to one of ordinary skill in the art.
Regarding claim 24, Stein teaches that the base component of the composition may include sodium bicarbonate (see Stein claim 7) and further teaches that more than one base may be used (see Stein claim 8). Sodium bicarbonate is a well-known pharmaceutically acceptable buffering salt used to stabilize pH in oral formulations. Accordingly Stein suggests the use of sodium bicarbonate in combination with EDTA and an additional base (such as lysozyme) and it would have been obvious to optimize the amount within the ranges taught in the prior art in the formulation for treatment of dental infections/gingivitis given it is a result effective variable.
Response to Applicant’s Arguments
Applicant argues that Stein discloses a composition containing lysozyme for oral care. However, a person of ordinary skill in the art would not combine Poulsen and Stein, and even if combined, they would not suggest the presently claimed methods. There would be no reason to combine the incompatible mechanisms of Stein and Poulsen. Stein relies on lysozyme (a muramidase that cleaves bacterial cell walls). Poulsen relies on a peroxide-generating enzymatic cascade (invertase glucose oxidase lactoperoxidase hypothiocyanite) that acts as a chemical oxidant. There is no motivation for a person of ordinary skill in the art to combine these two distinct, non-interacting, and mechanistically independent antibacterial systems. They represent alternative, not complementary, strategies. Combining them would result in a mere aggregation of components, not a single, unified invention. Furthermore, the references teach away from the combination. Poulsen's System is Substrate-Dependent - it requires the presence of sucrose to generate its antibacterial effect. Adding this complex, sugar-dependent system to Stein's lysozyme composition would be illogical, as it would render the product's efficacy dependent on dietary sugar intake, a significant disadvantage. In addition, there would be a risk of system interference. Introducing Poulsen's hydrogen peroxide (H₂O₂) generating system into a composition containing a delicate enzyme like lysozyme could potentially inactivate or destabilize the lysozyme, thereby reducing any efficacy of the original Stein composition. Moreover, the combined references do not achieve the inventive synergy. As defined in the specification, the invention relies on the synergy between lysozyme and a chelating agent (EDTA) in a specific pH range. Poulsen does not teach or suggest the use of EDTA for membrane disruption nor does it provide any motivation and use the lysozyme/chelator of the instant claims.
Applicant’s arguments have been fully considered but not found persuasive. Applicant argues that a person of ordinary skill in the art would not combine the teachings of Stein and Poulsen because the references rely on different antibacterial mechanisms. Applicant further argues that the peroxide-generating system of Poulsen could destabilize lysozyme and that the reference therefore teach away from the proposed combination. This argument is not persuasive.
The rejection does not rely on combining the peroxide generating cascade Poulsen with the lysozyme system of Stein for the purpose of producing peroxide mediated antimicrobial activity. Rather, Poulsen is cited for teaching antimicrobial oral compositions containing lysozyme and EDTA within ranges that overlap or render obvious the claimed ranges and for teaching buffered antimicrobial compositions suitable for oral administration. Furthermore, Boland teaches that EDTA enhances the antimicrobial activity of lysozyme by chelating divalent cations that stabilize bacterial membranes, thereby increasing bacterial susceptibility to lysozyme mediated cell wall degradation. Thus, the prior art recognizes that combining EDTA with lysozyme enhances antibacterial activity. Accordingly, a person of ordinary skill in the art would have been motivated to combine the antimicrobial compositions of Stein with the teachings of Poulsen and Boland in order to optimize antimicrobial efficacy in oral care compositions.
Applicant’s arguments that the peroxide system of Poulsen could destabilize lysozyme is unsupported by evidence. Attorney argument cannot take the place of evidence (see MPEP 716.01(c)). Moreover, the references do not teach away from the combination. A reference teaches away only when it criticizes or discourages the combination. Poulsen does not criticize or discourage the use of lysozyme or EDTA in antimicrobial compositions.
Applicants argue demonstration of unexpected results. Furthermore, the invention demonstrates unexpected results. The clinical data provided in the Comparative Clinical Study (Lysodent® VS. Chlorhexidine Digluconate 0.12%) submitted herewith demonstrates the superior efficacy of the claimed lysozyme/chelator/pH synergy. The clinical evidence demonstrates that the specific combination of lysozyme, EDTA, and pH buffering in the claimed ranges produces dramatically superior results compared to the closest prior art (chlorhexidine, the gold standard in oral antiseptics), including: Lysodent achieved a healthy gingival index in 3 days while chlorhexidine treated patients still had unhealth scores after 28 days (Figure 2). In dental surgery, Lysodent eliminated pain in 93-100% of patients from Day 1, whereas chlorohexidine, antibiotics and analgesics still let 86% of patients in pain on day 1 (see figure 3). Applicants argue unexpected synergistic effect via no need for additional medications, superior patient compliance with only 14% users reporting unpleasant taste compared to 88% for chlorohexdidine and no side effects. Applicants state the results demonstration commercial success and overcoming long felt need via effective broad spectrum antiseptics without antibiotics, rapid healing, powerful pain control and reduced side effects.
Applicant’s arguments have been fully considered but not found persuasive. First, the evidence presented is not directed to the closest prior art relied upon in the rejection under 35 U.S.C. 103. The rejection is based on references teaching lysozyme and chelating agents such as EDTA for antimicrobial purposes. The clinical data submitted by applicant compares the claimed composition to chlorhexidine, which is a different antiseptic compound and not the closest prior art combination of lysozyme and EDTA relied upon in the rejection. Evidence of unexpected results must be compared with the closest prior art in order to demonstrate nonobviousness (see MPEP 716.02 e). Because the submitted data does not compare the claimed composition to compositions containing lysozyme alone, EDTA alone or known combinations of lysozyme and EDTA taught by the prior art, the evidence does not establish that the alleged improvements would have been unexpected relative to prior art. Second, Applicant asserts that the claimed components exhibit synergistic activity. However, the submitted clinical study does not provide experimental controls demonstrating the activity of the individual components (e.g. lysozyme alone or EDTA alone). Without such comparisons, data does not demonstrate that the observed results arise from a synergistic interaction between the claimed components rather than from the known antimicrobial properties of the individual ingredients. Third, the submitted clinical data is not commensurate in scope with the claims. The study described in the specification involves treatment of gingivitis and poste dental surgery conditions in a limited patient population. However, the claims are directed broadly to methods of treating and preventing bacterial infections in a mammal using compositions containing lysozyme, EDTA and a pH stabilizing salt across broad concentration ranges. Evidence limited to dental applications doe s not demonstrate that the claimed composition would produce the asserted benefits across the full scope of bacterial infections encompassed by the claims. Evidence relied upon to rebut a prima facie case of obviousness must be commensurate in scope with the claims (see MPEP 716.02(d)). Additionally, the formulation used in the clinical study corresponds to a single composition containing approximately 36 mg lysozyme, 12 mg EDTA tetrasodium Salt and 2 mg sodium bicarbonate (Table 1). The claims, however, encompass much broader ranges of each component. The data therefore supports, at most, the performance of a single formulation within the claimed ranges, and does not demonstrate that the asserted advantages would be obtained across the full scope of the claimed compositions.
Claim(s) 21, 23-24, 28-30, 32-33, 35-36, 41 are rejected under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1) in view of Poulsen (WO8802600 A1) and Boland (Journal of Food Protection, Vol. 67, No. 2, 2004, Pages 285–294), as applied to Claim(s) 21, 23-24, 28, 35-36, 41 above in further view of Friedman (Therapeutic Mouthwash for Preventive and Post-Surgery Care, https://bestlincroftdentist.com/blog/therapeutic-mouthwash-preventive-post-surgery-care/, 2016).
The teachings of Stein in view of Poulsen are described above. The combined teachings are silent to using the oral care formulation during dental surgery or after dental surgery (including extraction surgery).
However, Stein in view of Poulsen teach the oral care formulations for use against bacteria in the mouth (see claims 25-26 of Stein for example) and also abstract of Poulsen (bactericidal composition). Poulsen teaches antibacterial activity against “of the genera streptococcus, Lactobacillus, Bacteroides, Flovobacterium and Fusobacterlum” (see examples 1-2).
Friedman teaches use of therapeutic mouthwash before (preventative) and post dental surgery (see title). Friedman teaches “Using mouthwash is part of your oral hygiene. It prevents tooth decay, controls plaque and freshens your breath. The liquid solution promotes oral hygiene, reduces oral discomfort, provides moisture to your oral tissue and prevents bad breath. It can be prescribed by your dentist or purchased from the drugstore or grocery. Dentists may prescribe special mouthwash to patients with severe oral problems, periodontal diseases, gums inflammation or dry mouth. It can be prescribed after an oral surgery or periodontal treatments like planning and scaling. This speeds up the healing process, reduces microbial load and eases any discomfort” (first two paragraphs).
It would have been obvious before the effective filing date of the claimed in invention to include use of the oral care formulation of Stein in view of Poulsen and Boland for treat prior to, during or after dental extraction surgery. One of ordinary skill in the art would have been motivated to do to prevent, inhibit or reduce bacterial load at the site of extraction in order to promote healing and prevent infection. There is a reasonable expectation of success given the formulation of Stein, Poulsen and Boland can be used as a wash and lysozyme and EDTA are shown to be effective antibacterial compounds for pathogenic bacteria in the mouth oral cavity.
Claim(s) 21, 23-24, 28, 35-41 are rejected under 35 U.S.C. 103 as being unpatentable over Stein (US20160030327 A1, cited previously) in view of Poulsen (WO8802600 A1, cited previously) and Boland (Journal of Food Protection, Vol. 67, No. 2, 2004, Pages 285–294), as applied to Claim(s) 21, 23-24, 28, 35-36, 41 above, in further view of Deaton (US20130101634, cited in Applicant’s IDS).
The teachings of Stein in view of Poulsen and Boland are provided in the above rejection. The combined references of Stein in view of Poulsen and Boland are silent to specifically at least 20% lysozyme, at least 20-80% lysozyme, at least 40-80% lysozyme. Stein teaches wherein the chelators EDTA (see claim 3) and in a concentration range of .0005-30% of the composition (see claim 5). Stein teaches wherein the base is lysozyme and/or sodium bicarbonate (see claim 7), in a concentration of 0.0001-15% of the composition (see claim 9) and where more than one base is used.
Deaton teaches a method of treating microbial growth comprising administering an antimicrobial composition (see abstract). Deaton teaches a composition for reducing microbial overgrowth comprising lysozyme (see paragraph 0089), EDTA (paragraph 0089) and citrate buffer (see paragraph 0061) which meets the limitations of a pH stabilizing salt. Deaton teaches that the lytic enzyme (aka the lysozyme) can be 30-40 wt% (see paragraph 0036). Deaton teaches that the chelating agent (such as EDTA) can be 10-20 wt% (see paragraph 0042). Deaton teaches that the compositions are for pharmaceutical purposes (see paragraph 0055) and oral administration (see paragraph 0054).
The concentration of antimicrobial components such as lysozyme and EDTA represent result effective variable (for antimicrobial activity), as the effectiveness of the antimicrobial compositions is known to depend on the concentration of the active agents. Deaton teaches that lysozyme may be present at 30-40 wt% and EDTA at 10-20%, which overlaps the ranges recited in instant claims 21, 23, 37-40. It would therefore would have been obvious to one of ordinary skill in the art to optimize the concentration of lysozyme and EDTA within the overlapping ranges taught by the prior art including the higher concentrations taught by Deaton, in order to achieve the desired antimicrobial activity in the oral cavity. Routine optimization of such result-effective variables would have been well within the ordinary skill in the art (see MPEP 2144.05 I-II).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654