CTNF 18/036,602 CTNF 101601 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status 2. Applicant’s election of Group II (claims 12-18) in the reply filed on March 10, 2026 is acknowledged. Claim 14 is presently amended. Therefore, claims 1-18 are presently pending, with claims 1-11 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse. Information Disclosure Statement 06-49-06 AIA 3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Objection to the Specification 4. The instant specification is objected to for the following reasons: a. There are trademarks in this application that do not meet the requirements. The use of the term e.g., “Leica” at para. [0102], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correction is required. b. There are references in this specification that should be placed on an information disclosure statement if application would like them considered. Claim Objections 5. Claims 12-18 are objected to for depending from the non-elected invention—independent claim 12 depends from claim 1. Appropriate correction is required. Claim Interpretation for the purpose of rejections based on the claim objection as set forth in paragraph 5: Claims 12-18 are method claims that depend from the non-elected formulation of claim 1. Therefore, the present method claims are being interpreted as incorporating every limitation of non-elected claim 1; i.e., wherein the pharmaceutical formulation administered to the patient comprises “an effective dose of annexin protein and a high concentration of phage, wherein the presence of the annexin protein reduces bacterial contamination and phage aggregation relative to a pharmaceutical formulation lacking annexin to produce a stabilized phage formulation.” Claim Rejections - 35 USC § 112 07-30-01 AIA 6. 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. Written Description 07-31-01 Claims 12-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.” The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that: "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.) No Written Description for the Breath of the Claims (“high concentration” of genus “phage”): The claims are directed to a method of treating bacterial infection with a pharmaceutical formulation comprising annexin protein and the genus “phage.” The claims recite that the phage is present in the formulation at a “high concentration;” that the phage has reduced aggregation in the formulation; and the treatment must result in bacterial lysis to resolve an infection. Claim 13 further recites that the high concentration is “greater than 10 8 pfu/ml.” The claims therefore broadly encompass methods of treating bacterial infection with pharmaceutical formulations comprising any “phage” type at any “high” concentration, and only more narrowly specifies the high concentration at claim 13. The claimed method must possess specific functions, including causing bacterial lysis to resolve the infection. However, there is no structure recited in the claims that would correlate with these functions. The specification only sets forth concentrations of phage greater than about 10 12 pfu/ml as potentially having the required bacterial lysis function at para. [0006]; and furthermore, only demonstrates the treatment of bacterial infection with the PAML31-1 phage at a titer of 3.75 x 10 15 phage/ml 1 at FIGs. 3-6. However, the PAML31-1 phage at a titer of 3.75 x 10 15 phage/ml is not sufficiently representative of such a broad genus of “phage” at “high concentration” as instantly claimed. The specification discloses that phage-induced “lysis from without” is rare at phage concentrations of 10 7 -10 8 pfu/ml; however, Applicant “found that a single dose of phage at concentrations > 10 12 pfu/ml can rapidly reverse lethal bacterial wound infections in mice.” See specification at para. [0087]. The only specific dose of phage disclosed as administer to treat a bacterial infection is at a titer of 3.75 x 10 15 phage/ml. See specification at para. [0092]. The specification is not clear as to what phage was administered, however presumably the administered “ 99m Tc-HYNIC labeled phage” was the PAML31-1 phage of para. [0090]. The specification does not disclose the administration of any other phage dosages other than PAML31-1 phage at a titer of 3.75 x 10 15 phage/ml. The claims recite functional language of the phage pharmaceutical formulation, such as causes bacterial lysis; however a definition by function does not suffice to define the genus because it is only an indication of what the pharmaceutical formulation does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of pharmaceutical formulations is highly variable (e.g., each pharmaceutical formulation having a different “phage” would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “high concentrations” of “phage” have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of phage-induced bacterial cell lysis is provided below, which shows that the genus “high concentration” of “phage” is highly variable with respect to efficacy for inducing bacterial cell lysis and thereby resolving a bacterial infection. Abedon ("Lysis from without." Bacteriophage 1.1 (2011): 46-49) is a commentary related to the instantly claimed method of using high concentrations of phage to lyse bacterial cells. Abedon at para. 1. Abedon teaches that “[m]ost phages do not cause lysis from without,” and that even phages from the classes of phage that do work (e.g., T-even phages) can have “resistance to lysis from without.” Abedon at introduction, molecular mechanisms. Abedon teaches that a titer of at least 10 9 phage/ml should be used, and suggests adjusting the concentration of phage if lysis is not experimentally observed. Abedon at assaying for LO v . Abedon concludes: “Importantly, not all attempts to demonstrate LO v [lysis from without] in specific phages have been successful” and further provides 31 references demonstrating failures to achieve lysis from without with various phage and bacteria combinations. Abedon therefore teaches that it is very unpredictable which “phage” at what “high concentration” will achieve bacterial lysis and successful treatment in different bacterial infections. Accordingly, significant experimentation is required to find combinations that are operable. Neither the art nor the specification provides a sufficient representative number of “high concentration of phage” species that lyse “bacteria” (see below regarding genus “bacteria”) to meet the written description requirement for instant claims directed to methods of treating bacterial infection with a pharmaceutical formulation comprising annexin protein and “high concentration of phage” in general. It is therefore unknown how the genus of a pharmaceutical formulation comprising annexin protein and “high concentration of phage” would lyse bacterial cells to resolve a bacterial infection. Applicant has not shown possession of a representative number of species that have the claimed function(s); and furthermore, the specification explicitly teaches that greater than about 10 12 pfu/ml is required . The specification therefore provides insufficient written description to support the genus of “high concentration” of “phage” encompassed by the claims. Given all of the above, Applicant does not have written description for method of treating a bacterial infection with a pharmaceutical formulation comprising “high concentration” of “phage.” No Written Description for the Breath of the Claims (method of treating genus “bacterial infection”): As noted above, the claims recite a method for treating genus “bacterial infection.” Claim 16 additionally recites a laundry list of gram-negative bacteria including Pseudomonas aeruginosa . The claims therefore encompass treating any type of bacterial infection with the claim-recited phage formulation. In contrast, the specification only demonstrates the treatment of a Pseudomonas aeruginosa bacterial infection with the PAML31-1 phage at a titer of 3.75 x 10 15 phage/ml 2 at FIGs. 3-6. As discussed above, Abedon provides 31 references demonstrating failures to achieve lysis from without with various phage and bacteria combinations highlighting the unpredictability of pairing “phage” with “bacteria” to produce bacterial lysis to resolve an infection. A brief assessment of the first of these 31 references (Uchiyama et al.) is provided herein, which further shows it is highly unpredictable which phage / concentration will lyse what bacteria: Uchiyama et al. ("Isolation and characterization of a novel Enterococcus faecalis bacteriophage φEF24C as a therapeutic candidate." FEMS Microbiology letters 278.2 (2008): 200-206) is directed to a search for candidate therapeutic phages against Enterococcus faecalis infections. Uchiyama et al. at abstract. Uchiyama et al. teaches: “Moreover, although most phages display host specificity to particular bacterial species and strains, some phages can infect more than one species of bacteria (i.e. polyvalent phage). However, φEF24C showed neither lysis activity nor lysis-from-without activity against the tested bacteria other than Enterococcus faecalis (10 Enterococcus faecium strains, two S. aureus strains, and one Escherichia coli strain). Thus, φEF24C seems to be specific to only Enterococcus faecalis .” Uchiyama et al. at infection activity of phage φEF24C. Therefore, Uchiyama et al. teaches species: φEF24C phage can only lyse species: Enterococcus faecalis bacteria. Therefore, it is highly unpredictable which members of claim-recited genus “phage” will lyse which members of genus “bacteria” without performing the required experiments. Neither the art nor the specification provides a sufficient representative number of phage that lyse genus “bacteria” to meet the written description requirement for instant claims directed to methods of treating “bacterial infection” with a pharmaceutical formulation comprising annexin protein and high concentration of phage in general. It is therefore unknown how the genus of a pharmaceutical formulation comprising annexin protein and high concentration of phage would lyse bacterial cells to “resolve a bacterial infection.” Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of bacterial infections encompassed by the claims. Given all of the above, Applicant does not have written description for method of treating a “bacterial infection” with a pharmaceutical formulation comprising “high concentration” of “phage.” No Written Description for the Breath of the Claims (“effective dose” of genus “annexin protein”): The claims are directed to a method of treating bacterial infection with a pharmaceutical formulation comprising “an effective dose of annexin protein” and phage. The claims recite that the presence of the annexin protein reduces bacterial contamination and phage aggregation relative to a pharmaceutical formulation lacking annexin to produce a stabilized phage formulation. The claims therefore broadly encompass methods of treating bacterial infection with pharmaceutical formulations comprising: (i) any “annexin protein,” including any annexin family member and variants thereof; at (ii) any concentration; to stabilize the phage formulation. The claimed method must possess specific functions, including (i) reducing bacterial contamination, (ii) reducing phage aggregation, and (iii) stabilizing the phage formulation. However, there is no structure recited in the claims that would correlate with these functions. The specification only sets forth and demonstrates Annexin V at a concentration of 0.1 mg/ml as potentially having the required functions. However, Annexin V at a concentration of 0.1 mg/ml is not sufficiently representative of such a broad genus of “annexin protein” as instantly claimed. The specification discloses that addition of an effective amount of Annexin V (0.1 mg/ml) stabilized three different phage formulations at FIG. 7. The specification teaches at para. [0086]: “Annexin V is a safe enzymatically inert human protein that binds to Lipid A/lipopolysaccharide (LPS) bacterial membrane contaminants and negatively charged chemical species (i.e. N-glycans) within the phage protein coat, to prevent aggregation, simplify purification and stabilize phage preparations at high enough phage titer (> 10 12 /ml) to directly lyse target bacteria following administration in contrast to low titer (10 7 to 10 8 /ml) phage infection/replication protocols used in clinical trials which often require weeks of daily injections.” The specification does not disclose that any other annexin proteins or concentrations were used, let alone that another annexin protein and/or concentration that stabilized a phage formulation. The claims recite functional language of the effective dose of annexin protein, such as (i) reducing bacterial contamination; (ii) reducing phage aggregation; and (iii) stabilizing the phage formulation; however, a definition by function does not suffice to define the genus because it is only an indication of what the “effective dose of annexin protein” does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of annexin protein is highly variable (i.e., each annexin protein would necessarily have a unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “annexin proteins” have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of “annexin proteins” binding to lipids is provided below, which shows that the genus “annexin protein” is highly variable with respect to efficacy for binding to lipids and therefore reducing bacterial contamination and stabilizing a phage formulation. Wang et al. ("Domain IV of annexin A5 is critical for binding calcium and guarantees its maximum binding to the phosphatidylserine membrane." Molecules 22.12 (2017): 2256) is a research article investigating the importance of Annexin V domains to phosphatidylserine (PS) binding. Wang et al. at abstract. Wang et al. shows: “Conclusions: Truncation of domain IV of anxA5 destroys its calcium-binding ability and impairs its PS-binding activity.” Id. Therefore, truncations / fragments of Annexin V can destroy its ability to bind to lipid and thereby reduce bacterial contamination and stabilizing a phage formulation. Jing ("The relevance, predictability, and utility of annexin A5 for human physiopathology." International journal of molecular sciences 25.5 (2024): 2865) is a review article focused on Annexin V. Jing et al. at title. Jing et al shows that the domain structures of Annexins 1-13 are substantially different at FIG. 1, and the importance of 8 amino acids for the function of Annexin V, e.g., for lipid binding at Table 1. Therefore, variants of Annexin V may not bind to lipid and thereby reduce bacterial contamination and stabilize a phage formulation. Rosenbaum et al. ("Identification of novel binding partners (annexins) for the cell death signal phosphatidylserine and definition of their recognition motif." Journal of Biological Chemistry 286.7 (2011): 5708-5716) is a research article characterizing five members of the annexin family for their ability to bind to PS. Rosenbaum et al. at abstract. Rosenbaum et al. shows: “The results showed that AnxA3, AnxA4, AnxA13, and the already described interaction partner AnxA5 can bind to phosphatidylserine and apoptotic cells, whereas AnxA8 lacks this ability.” Id. Therefore, other species of “annexin protein” (e.g., Annexin 8) cannot bind to lipid and thereby reduce bacterial contamination and stabilize a phage formulation. The cited references therefore teach that it is very unpredictable what “annexin protein” will sufficiently bind to lipid—and at what concentrations (e.g., the above references demonstrate the encompassed annexin proteins have varying affinity for lipid)—to thereby reduce bacterial contamination and stabilize a phage formulation. Accordingly, significant experimentation is required to find “annexin proteins” and concentrations that will work. Neither the art nor the specification provides a sufficient representative number of “annexin protein” species that sufficiently bind to lipid compared to the WT Annexin V at 0.1 mg/ml demonstrated in the specification to meet the written description requirement for instant claims directed to a method of treating bacterial infection with a pharmaceutical formulation comprising “annexin protein” and a high concentration of phage, wherein the presence of the annexin protein reduces bacterial contamination and phage aggregation relative to a pharmaceutical formulation lacking annexin to produce a stabilized phage formulation. It is therefore unknown how the genus of “annexin protein” would bind to lipids and thereby reduce bacterial contamination and stabilize the pharmaceutical formulation also comprising a high concentration of phage. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of “annexin proteins” encompassed by the claims. Given all of the above, the cited reference therefore demonstrate that Applicant is not in possession of: a method of treating bacterial infection with a pharmaceutical formulation comprising “an effective dose annexin protein” and a “high concentration of phage.” Applicant is in possession of: a method of treating a Pseudomonas aeruginosa infection with a pharmaceutical formulation comprising 0.1 mg/ml Annexin V and >10 12 pfu/ml PAML31-1 phage. MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed. 07-30-02 AIA 7. 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. 07-34-01 Claim 13 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 13 is drawn to the method of claim 12, “wherein the amount of phage administered is greater than 10 8 pfu/ml.” The unit plaque-forming units (pfu) per ml is a concentration; without further specifying the volume administered, it is unclear what “amount” of phage the claim requires to be administered. Appropriate clarification and/or correction is required, i.e., replacing the word “amount” with “concentration.” Claim Rejections - 35 USC § 103 07-20-aia AIA 8. 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. 07-23-aia AIA 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. 07-20-02-aia AIA 9. 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. 07-21-aia AIA 10. Claims 1 2-18 are re jected under 35 U.S.C. 103 as being unpatentable over Ro se et al. ("Experimental phage therapy of burn wound infection: difficult first steps." International journal of burns and trauma 4.2 (2014): 66) in view of Arnold et al (Critical Care Medicine, January 2014, Volume 42, Number 1, pages, e32-e41). Cl aim 12 is drawn to a method of treating a bacterial infection in a subject, the method comprising: administering to the subject the pharmaceutical formulation of claim 1 (i.e., a pharmaceutical formulation comprising: an effective dose of annexin protein and a high concentration of phage, wherein the presence of the annexin protein reduces bacterial contamination and phage aggregation relative to a pharmaceutical formulation lacking annexin to produce a stabilized phage formulation) to cause bacterial lysis to resolve the infection. Claim 13 is drawn to the method of claim 12, wherein the amount of phage administered is greater than 10 8 pfu/ml. Claim 14 is drawn to the method of claim 12, wherein the bacterial infection is caused by a bacterium that is resistant to antibiotics. Claim 15 is drawn to the method of claim 1, wherein the bacterial infection is caused by a gram-negative bacterium. Claim 16 is drawn to the method of claim 15, wherein the gram-negative bacterium is selected from Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Campylobacter jejuni, Neisseria gonorrhoeae, Salmonella Typhi, nontyphoidal Salmonella, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, and Pseudomonas aeruginosa. Claim 17 is drawn to the method of claim 1, wherein the pharmaceutical formulation is administered locally at the site of infection. Claim 18 is drawn to the method of claim 1, wherein the pharmaceutical formulation is administered systemically. NOTE: annexin 5 and annexin V are the same protein. Rose et al. teaches methods of treating bacterial infection caused by Pseudomonas aeruginosa or Staphylococcus aureus in burn subjects by administering phages (a phage cocktail) to wounds of subjects that were resistant to a least three classes of antibiotics. Rose et al. at abstract, methods. Rose et al. discloses that the phage cocktail consisting of P. 68 aeruginosa phages 14/1 ( Myoviridae ) and PNM ( Podoviridae ) and S. aureus phage ( Myoviridae ), at a concentration of 10 9 plaque forming units (pfu)/ml of each phage (high concentration phage), was produced and purified of endotoxin. Id. Rose et al. suggests that antibiotic resistance has become a major public health problem and the antibiotics pipeline is running dry and bacteriophages (phages) may offer an innovative means of infection treatment which can be combined or alternated with antibiotic therapy may enhance our abilities to treat bacterial infections successfully. Id. Rose et al. teaches that in burn units, a large number of infections are virtually untreatable. Rose et al. at introduction. Whereas Staphylococcus aureus remains a common early colonizer of burn wounds, Pseudomonas aeruginosa is known as the most common cause of life-threatening infection in burn patients. Id. Both bacteria, but especially P. aeruginosa , are known for their intrinsic and acquired resistance to many antibiotics. Id. Persistent multidrug-resistant P. aeruginosa strains have frequently been reported to cause nosocomial outbreaks of infection in burn units. Id. Rose et al. teaches that bacteriophages are among the most abundant and ubiquitous organisms on Earth and are the natural controllers of bacteria. Id. Rose et al. cites a number of cases where phages have rescued (treated) burn subjects from bacterial infections. Id. Rose et al. also cites cases where phages were used in addition to antibiotics. Id. Given all of the above, Rose et al. teaches that high concentration bacteriophages are used to treat antibiotic resistant bacterial infections. Rose et al. does not explicitly disclose systemic administration of a phage and annexin V protein; or that annexin protein may stabilize a phage formulation. Arnold et al. teaches a method of treating endotoxemia and sepsis by treating subjects with the administration of annexin 5 (annexin V / annexin A5) intravenously (systemically). Arnold et al. at abstract. Arnold et al. teaches sepsis is a systemic inflammatory response to infection with an estimated 18 million cases annually worldwide and is a leading cause of in-hospital death. Arnold et al. at introduction. Arnold et al. teaches that hospitalizations for sepsis have doubled over the last 10 years and have overtaken those for myocardial infarction. Id. Sepsis is characterized by excessive proinflammatory cytokine production in response to bacterial infection. Initiation of the host’s innate immune response is mediated through activation of pattern recognition receptors such as toll-like receptor (TLR) 2 and 4 for gram-positive and negative bacterial infections. Id. Arnold et al. teaches that annexin A5 is a 35-kDa phospholipid binding protein and a member of the 13 annexin protein family. Id. Arnold et al. teaches that TNF-α is a major contributing factor to cardiac dysfunction leading to high mortality in severe sepsis and septic shock. Id. Arnold et al. teaches that annexin A5 has been shown to interact with cell receptors and inhibit their function by binding to leucine-rich repeats through a conserved N-terminal sequence. Id. Interestingly, the LPS binding region of the extracellular domain of TLR4 receptors contains 21 separate leucine-rich repeats. Id. It is possible that annexin A5 may inhibit LPS binding to TLR4 receptors via its interaction with the leucine-rich repeats, leading to decreases in downstream MAPK signaling. Id. In the present study, Arnold et al. hypothesized that annexin A5 improves cardiac function and animal survival during sepsis by inhibiting LPS binding (reducing aggregation and contamination) to the TLR4/myeloid differentiation factor 2 (MD-2) receptor complex. Id. Arnold et al. demonstrates that treatment with annexin A5 decreased myocardial TNF-α expression and improved cardiac function and survival in mice with endotoxemia and suggest that Anx5 may have novel therapeutic potential in sepsis. Id. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to combine the method of treating bacterial infection (burn wound infections) with the high concentration phages as disclosed by Rose et al. with the method of treating bacterial infection (i.e., sepsis caused by bacterial infection, improves cardiac function caused by sepsis and survival of subjects during endotoxemia (specifically lipopolysaccharides or LPS in the bloodstream)) by administering annexin V as taught by Arnold et al to produce stable pharmaceutical composition because both bacteriophages and annexin V had been shown to treat bacterial infections. The court held in In re Kerkhoven , 205 USPQ 1069 (CCPA 1980) that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose (i.e., treating bacterial infections). The idea of combining them flows logically from them having been individually taught in the prior art. There is a reasonable expectation of success that combining one individual bacterial treatment with another would result in a third beneficial bacterial infection treatment. Given all of the above, Arnold et al. teaches that annexin A5 is used to treat bacterial infection by interacting with cell receptors and inhibit their function by binding to leucine-rich repeats, thereby inhibiting LPS binding to TLR4 receptors. Furthermore, it is obvious to apply a known technique (i.e. treating bacterial infection with annexin protein) to a known method (i.e., treating bacterial infection with a high amount of phage) that is ready for improvement to yield predictable results. Here, the base method is treating bacterial infection with a high amount of phage (e.g., Rose et al.), upon which the claimed invention can be seen as an “improvement.” The prior art, e.g., Arnold et al., contains a known technique (i.e., treating bacterial infection with annexin protein) that is applicable to the base method because it targets the same problem—treatment of bacterial infection—through a complementary pathway. One of ordinary skill in the art would have recognized and appreciated that applying the known technique of treating bacterial infection with annexin protein to the known method of treating bacterial infection with high amount of phage would have yielded the predictable result of improved treatment of bacterial infection. Although the claims recite additional limitations, such as that the formulation used in the method is a “stabilized phage formulation,” these limitations are necessarily present in the prior art because they describe physical properties that will result from combining annexin and phage bacterial infection treatments, as motivated by the prior art. Therefore, claims 12-18 are rendered obvious by Rose et al. in view of Arnold et al. Pertinent Art 07-96 AIA 11. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure : Blankenberg (US 20190008922 A1, published January 10, 2019); further discloses use of annexin V for treating bacterial infections. Conclusion 12. No claim is allowed. 13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at 20857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /BRANDON R SCHWECHTER/ Examiner, Art Unit 1674 /VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674 Application/Control Number: 18/036,602 Page 2 Art Unit: 1674 Application/Control Number: 18/036,602 Page 3 Art Unit: 1674 Application/Control Number: 18/036,602 Page 4 Art Unit: 1674 1 The specification at para. [0092] describes treating mice with 250 µl of 99m Tc-HYNIC labeled phage, with 9.38x10 14 labeled phage per dose. Since there is 1000 µl in a ml, multiplying 9.38x10 14 by 4 results in a concentration of 3.75 x 10 15 phage/ml. 2 The specification at para. [0092] describes treating mice with 250 µl of 99m Tc-HYNIC labeled phage, with 9.38x10 14 labeled phage per dose. Since there is 1000 µl in a ml, multiplying 9.38x10 14 by 4 results in a concentration of 3.75 x 10 15 phage/ml.
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