CTNF 18/252,171 CTNF 101611 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 12-151 AIA 26-51 12-51 Status of Claims Amendment filed on Jan 12, 2026 is acknowledged. Claims 3-4 and 16-20 are withdrawn. Claims 8 and 9 are currently amended. Claims 1-2 and 5-15 are pending and under consideration. It should be noted that claims 16-20 have improper claim status identifiers. Said status identifiers must be corrected for any response to this Office to be deemed fully responsive. Information Disclosure Statement The information disclosure statement (IDS) filed on 10/16/2024 is considered, initialed and are attached hereto. Priority Applicant’s claim for benefit of and priority to U.S. provisional patent application 63/111,320, filed November 9, 2020, is acknowledged. The subject matter of claims 9 and 10 are not included in the provisional application 63/111,320, and therefore the priority is not granted. The priority of claims 9 and 10 are the effective filing date of November 9, 2021. Election/Restriction 08-25-01 AIA Applicant’s election without traverse of Group I (claims 1-2 and 5-15) in the reply filed on Jan 12, 2026 is acknowledged. Applicant's election with traverse of species requirement in the reply filed on Jan 12, 2026 is acknowledged. The traversal is on the ground(s) that the disclosed species are not patently distinct as claimed and because the claims include generic subject matter. 08-06 AIA Claim 3-4 and 16-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Jan 12, 2026 . The requirement is still deemed proper and is therefore made FINAL . 08-21-04 AIA Applicant’s comments regarding rejoinder are noted. Applicant is respectfully reminded that where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined. In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01. Under further consideration, the requirement for election of species is withdrawn. Claim Objections Claims 1 and 2 are objected to for using the acronym “PF4” without defining its proper name at its first occurrence in the claims. Claim Rejections - 35 USC § 112 07-30-02 AIA 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 Claims 1-2 and 5-15 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. Claims 1 and 2 are rendered vague and indefinite by the use of the term “PF4”. Said term constitutes a laboratory designation which conveys not particular structure. Consequently, it is impossible to determine the metes and bounds of the claimed invention. Correction is required. Claim 15 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 15 recites “non-antibiotic antibacterial substance”. The specification at page 4, paragraph [0018] recites “as used herein, the term “non-antibiotic antibacterial substance includes synthetic antibacterial substances, for example, sulfonamides or antiseptics”. This is an opened end definition that does not the define “non-antibiotic antibacterial substances”. Correction is required. Written Description 07-30-01 AIA 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. 07-31-01 Claims 1-2 and 5-15 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The 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 Applicant was in possession of the claimed genus. In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicant are claiming and what Applicant have possession of. The claims are drawn to a method of treating, inhibiting or reducing the severity of a bacterial infection in a subject in need thereof, the method comprising administering PF4 to the subject. The bacterial infection can be caused by Gram-negative bacteria or Gram-positive bacteria. The bacteria is antibiotic-resistant, to at least one antibiotic selected from the group consisting of: penicillin, oxacillin, methicillin, and amoxicillin-clavulanic. The subject could develop sepsis and peritonitis from the bacterial infection. The method could further comprises administering an antibiotic compound, a non-antibiotic antibacterial substance, and/or a glucocorticoid. The specification teaches the term "subject" refers to a multi-cellular vertebrate organism, including human and non-human mammals, for example, mice (instant specification paragraph 19). The specification teaches “inhibiting a bacterial infection” refers to reducing the quality, amount, or strength of viable bacteria in an infected subject, such as reducing the biological activities of the microorganisms (instant specification paragraph 20). The specification teaches "reducing the severity of a bacterial infection" refers to reducing the quality, amount, or strength of viable bacteria in an infected subject and to reducing the mortality rate of a bacterial infection (instant specification paragraph 21). The specification teaches the term "non-antibiotic antibacterial substance" includes synthetic antibacterial substances, for example, sulfonamides or antiseptics (instant specification paragraph 18). Regarding to PF4, the specification teaches it includes human Platelet Factor 4 (PF4, UniProtKB-P02776) and recombinant PF4 as set forth in the instant specification paragraphs 7 and 22. The speciation fails to teach if the recombinant PF4 protein is modified or different from the native human PF4 protein. Therefore PF4 is interpreted encompassing modified PF4 proteins that are different from the native protein UniProtKB-P02776, such as proteins produced in simple organisms that lack post-translational modifications, proteins folded differently from the native protein, or proteins engineered to include affinity tags to improve production and/or purification. In addition, the claims also broadly encompass all modification to PF4 protein, including all fragments, variants and derivatives. Therefore, the claims PF4 would encompass infinite numbers of PF4 protein. The specification does not provide adequate written description to identify the broad and variable genus of the PF4 because, inter alia, the specification does not disclose a correlation between the necessary structure of the protein and the function(s) recited in the claims. A definition by function does not suffice to define the genus because it is only an indication of what the 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. Further, given the highly diverse nature of proteins, even one of skill in the art cannot envision the structure of the PF4. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing infinite number of PF4 proteins claimed only by a functional characteristic and/or partial structure. Furthermore, Applicant has not shown procession of a representative number of species that have the claimed function(s). The specification has written description for the human PF4 and a recombinant PF4 protein as set forth in the specification paragraphs 7 and 22. As noted above, Applicant fails to teach the structure of the recombinant PF4 protein used in the examples. Therefore, it is unclear the structure of the PF4 essential for the claimed function. However, the claims are not limited to these exemplary PF4 proteins, and encompass the native PF4 protein, recombinant protein that are different from the native protein, and its fragments, variants and derivatives. Thus the genus has substantial variation because of the numerous alternatives. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only two species have been described and this is not considered to be representative of the breadth of the genus. Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al (PLoS Comput Biol 4(10): e1000160, 2008) teaches that homology (both orthology and paralogy) does not guarantee conservation of function. Relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (pg. 2). It is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (pg. 2). Punta et al. also teaches that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (pg. 2, tab. 2). Proteins live and function in 3D, and therefore structural information is very helpful for predicating function (pg. 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (pg. 4). Punta et al teaches that still structural knowledge is an extremely powerful tool for computational function prediction (pg. 5). Similarly, Whisstock et al (Quarterly Reviews in Biophysics. 36(3):307-340, August 2003) teaches that the prediction of protein function from sequence and structure is a difficult problem (abs.). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (pg. 309). Moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (pg. 309). Further, even sequences that are the same can have different functions. For example, eye lens proteins in the duck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (pg. 310). Whisstock et al. teaches that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (pg. 321). Whisstock et al. further teaches that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (pg. 321-323). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. Cell Biol. 111:2129-2138, 1990) who teaches that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (pg. 1287-1289). Moreover, Defeo-Jones et al (Molecular and Cellular Biology, Sept. 1989, pg. 4083-4086) teaches that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (abs., pg. 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein. Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (pg. 398 col. 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (pg. 398 col. 2). Conclusions from the comparison analysis are often stretched with regard to protein products (pg. 398 col. 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (pg. 399 col. 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (pg. 399 tab.1 legend). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (pg. 399, col. 2 & 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (pg. 400, section Taking the 70% Hurdle). Given not only the teachings of Punta et al, Whisstock et al, Song et al, Burgess et al, and Defeo-Jones et al, but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the protein per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities. Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Additionally, the claims recite administering PF4 to treat, inhibit all bacterial infection, or reduce the severity of all bacterial infection caused by all strains of bacteria (or all strains of Gram-negative bacteria, or all strains of Gram-positive bacteria, or all strains of bacteria that are resistant to antibiotics), in all multi-cellular vertebrate organisms. The specification has written description for following examples: (1) administering a recombinant PF4 to a mouse S. aureus peritonitis and sepsis model treats or inhibits the S. aureus infection and reduces the severity of the S. aureus infection in mice (examples 1&3) ; and (2) administering a recombinant PF4 to a mouse S. aureus peritonitis and sepsis model inhibits the methicillin-resistant S. aureus infection in mice (example 4). The specification does not have written description to treat or inhibiting infection caused by all bacteria in all multi-cellular vertebrates. The specification also does not have written description to treat or inhibiting infection caused by all bacteria in any multi-cellular vertebrates who develop sepsis or peritonitis from all bacterial infection. The claimed invention encompasses administering PF4 or its fragments, variants and derivatives, to treat all types of bacterial infection, including sepsis and peritonitis, in all multi-cellular vertebrates. A brief assessment of the state the art regarding the claims is made herein. First, PF4 might not be able to kill or inhibit growth of all bacteria. For instance, Wolff et al (J. Thromb. Haemost. 18 (6): 1459-1468, published June 2020) teaches despite PF4 bind with both Staphylococcus aureus and Streptococcus pneumoniae , platelets or platelet releasate, which includes PF4, kills Staphylococcus aureus but not Streptococcus pneumoniae (Abstract, page 1460 left column 2 nd paragraph, also see sections 3.1 & 3.3). Second, PF4 plays a role in a variety of inflammatory diseases, such as pneumonia, malaria, hepatitis and atherosclerosis, acting as both a pro-inflammatory and an anti-inflammatory mediator (Ji et al. J Inflamm Res. 2025: I8, Pages 4481-4495). Therefore, “it is important to recognize that PF4 may target different organs and physiological environments, potentially exhibiting opposing regulatory effects, which can result in divergent roles in either promoting or inhibiting disease progression” (Ji et al. page 4481 1 st paragraph). Specifically in bacterial infection, PF4 binding to microbial polyanions, such as lipoteichoic acids on Gram-positive bacteria and lipopolysaccharide (LPS) on Gram-negative bacteria, may improve outcomes in infection by flagging bacteria for immune recognition, enhancing leukocyte-bacterial binding, tethering pathogens to neutrophil extracellular traps (NETs), decreasing the thrombotic potential of NET DNA, and boosting antibacterial activity of platelets (Ngo et al, Current Opinion in Hematology 30(6):p 219-229, November 2023). However, antibodies directed against PF4 not only help to clear infection but can also lead to the development of thrombotic disorders such as heparin-induced thrombocytopenia (HIT) (pages 219-223). The effect of PF4 in sepsis treatment is also unpredictable. Human sepsis is characterized by a set of systemic reactions in response to intensive and massive infection that failed to be locally contained by the host, and there are two established haemodynamic phases that may overlap: the initial phase (hyperdynamic) and the second phase (hypodynamic) (Toscano et al. JoVE. 2011 May 7; (51): 2860). Because both phases of sepsis may cause irreversible and irreparable damage, it is essential to determine the immunological and physiological status of the patient (Toscano et al, Abstract). The same drug given at different stages of sepsis may be therapeutic or otherwise harmful or have no effect and this is the main reason why many therapeutic drugs have failed (Toscano et al, Abstract). For instance, in the mouse CLP (cecum ligation and puncture model of polymicrobial sepsis) model, while PF4 might be beneficial in sepsis treatment (Poncz et al, WO 2020/055597 A1, published March 19 2020, example 6, Figure 13D), inhibiting PF4 (anti-CXCL4) has protective effect in the lung of the septic animals (Hwaiz et al. BJP. 2015. Volume172, Issue22. Pages 5347-5359). In fact, Xu et al (Autoimmunity. 2020 Aug;53(5):289-296. Epub 2020 Jun 13.) shows the serum level of PF4 (CXCL4) is upregulated in patients with sepsis, and the neutralizing antibody anti-PF4 (anti-CXCL4) improves the survival of mice in a mouse sepsis model. The disparity between the animal models of sepsis and human likely contributes to the unpredictability of translating the preclinical success to clinical setting - thousands of preclinical trials performed over more than five decades have failed to find more than a handful of drugs and techniques that significantly improve outcomes in clinical sepsis (Dyson and Singer, Critical Care Medicine 37(1):p S30-S37, January 2009). There are multiple animal models of sepsis, such as administration of endotoxin, live bacteria and abdominal sepsis, but they still differ markedly from human sepsis in severity of insult, species, age, gender, comorbidity, as well as physiologic and pharmacologic support, which are possible reasons why the benefits in animal models of sepsis fail to translate to the clinical setting (Dyson and Singer, p. S31-S34). Taken together, the state-of-the-art support the position that while PF4 has anti-microbial effect in vitro and in vivo , its effect in treating or inhibiting all bacterial infection, or reducing the severity of all bacterial infection, in all multi-cellular vertebrates, including who develop sepsis, is uncertain, due to the multiple roles of PF4 in immune system. Therefore, neither the art nor the specification provides a sufficient representative number of species to meet the written description requirement. 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.) University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966. 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. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15-fti Claim s 1-2, 5-6, 11, 13 and 15 rejected under pre-AIA 35 U.S.C. 102 (a)(1) and 102(a)(2) as being anticipated by Poncz et al (WO 2020/055597 A1, published March 2020, refer to as Poncz thereafter) . Claim 1 is drawn to a method of treating or inhibiting a bacterial infection in a subject in need thereof, the method comprising administering PF4 to the subject. Poncz teaches a method of using PF4 alone or anti-PF4 antibodies alone or the combination thereof to treat sepsis (Abstract). Poncz also teaches sepsis is caused by an immune response triggered by an infection, and most commonly, the infection is bacterial (page 22 line 12-25). In addition, Poncz teaches in a mouse model of CLP (cecum ligation and puncture model of polymicrobial sepsis) injury, PF4 at 40 mg/kg decreases MSS (mouse sepsis scores) at 48 hours after the injury (example 6, Figure 13D). (page 22, line 12-25). Claim 2 is drawn to a method of reducing the severity of a bacterial infection in a subject in need thereof, the method comprising administering PF4 to the subject. Poncz teaches a method of using PF4 alone or anti-PF4 antibodies alone or the combination thereof to treat sepsis (Abstract), and sepsis is caused by an immune response triggered by an infection, and most commonly, the infection is bacterial (page 22 Iine 12-25). In addition, Poncz teaches in a mouse model of CLP (cecum ligation and puncture model of polymicrobial sepsis) injury, PF4 at 40 mg/kg decreases MSS (mouse sepsis scores) at 48 hours after the injury (example 6, Figure 13D). Claims 5&6 are drawn to the method of claim 1, wherein the bacterial infection is caused by Gram-negative bacteria (claim 5) or by Gram-positive bacteria (claim 6). Poncz teaches the method of claim 1, and further teaches the bacterial infection is caused by Gram-negative bacteria or Gram-positive bacteria: in a mouse model of CLP (cecum ligation and puncture model of polymicrobial sepsis) injury, PF4 at 40 mg/kg decreases MSS (mouse sepsis scores) at 48 hours after the injury (example 6, Figure 13D). CLP polymicrobial sepsis model is established by puncturing the cecum and extruding a small amount of feces, and the mice tested are on C57Bl6 background (page 77 line 26, page 78 line 21-30, example 6). Feces of commonly used laboratory mouse strains include both Gram-negative and Gram-positive bacteria. Claim 11 is drawn to the method of claim 1, wherein the subject developed sepsis from the bacterial infection. Poncz teaches the limitation of claim 1, and further teaches the subject develops sepsis from the bacterial infection as explained above (Abstract; page 22 Iine 12-25). Claim 13 is drawn to the method of claim 1, wherein the subject developed peritonitis from the bacterial infection. Poncz teaches the limitation of claim 1, and further teaches the subject developed peritonitis from bacterial infection because the mouse model used, CLP (cecum ligation and puncture model, see example 6, Figure 13D), is a septic peritonitis model. Claim 15 is drawn to the method of claim 1, further administering to the subject an antibiotic compound, a non-antibiotic antibacterial substance, and/or a glucocorticoid. Poncz teaches the limitation of claim 1, and teaches the method may further comprise treating said subject with a second therapy, such as an antibiotic (page 3 line 25-27). Poncz also teaches their invention can be used to treat trauma, which includes common surgical procedure or settings that uses a sterile environment, anesthesia, antiseptic conditions (page 27 line 5-20). Antiseptic conditions is created by using antiseptics, which is a non-antibiotic antibacterial substance (see instant specification paragraph 18) . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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 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 Claim (s) 1-2 and 5-15 are rejected under 35 U.S.C. 103 as being unpatentable over Poncz (WO 2020/055597 A1, published March 2020, referred to as Poncz thereafter) in view of Yeaman et al (US 2013/0244928, published Sep 19, 2013, refer to as Yeaman thereafter) . Claim 1 is drawn to a method of treating or inhibiting a bacterial infection in a subject in need thereof, the method comprising administering PF4 to the subject. Claim 2 is drawn to a method of reducing the severity of a bacterial infection in a subject in need thereof, the method comprising administering PF4 to the subject. Claims 5&6 are drawn to the method of claim 1, wherein the bacterial infection is caused by Gram-negative bacteria (claim 5) or by Gram-positive bacteria (claim 6). Claim 7 is drawn to the method of claim 6, wherein the bacterial infection is caused by Staphylococcus aureus . Claim 8 is drawn to the method of claim 1, wherein the bacterial infection is caused by antibiotic-resistant bacteria. Claim 9 is drawn to the method of claim 8, wherein the antibiotic-resistant bacteria are resistant to at least one antibiotic selected from the group consisting of: penicillin, oxacillin, methicillin, and amoxicillin-clavulanic. Claim 10 is drawn to the method of claim 8, wherein the antibiotic-resistant bacteria is methicillin-resistant S. aureus . Claim 11 is drawn to the method of claim 1, wherein the subject developed sepsis from the bacterial infection. Claim 12 is drawn to the method of claim 11, wherein the bacterial infection is caused by S. aureus . Claim 13 is drawn to the method of claim 1, wherein the subject developed peritonitis from the bacterial infection. Claim 14 is drawn to the method of claim 13, wherein the bacterial infection is caused by S. aureus . Claim 15 is drawn to the method of claim 1, further administering to the subject an antibiotic compound, a non-antibiotic antibacterial substance, and/or a glucocorticoid. Poncz teaches a method of using PF4 alone or anti-PF4 antibodies alone or the combination thereof to treat sepsis (Abstract), and sepsis is caused by an immune response triggered by an infection, and most commonly, the infection is bacterial (page 22 Iine 12-25). In addition, Poncz teaches in a mouse model of CLP (cecum ligation and puncture model of polymicrobial sepsis) injury, PF4 at 40 mg/kg decreases MSS (mouse sepsis scores) at 48 hours after the injury (example 6, Figure 13D). The CLP model is a septic peritonitis model. This is relevant to claims 1, 2, 11 and 13. Poncz also teaches the CLP polymicrobial sepsis model is established by puncturing the cecum and extruding a small amount of feces, and the mice tested are on C57Bl6 background (page 77 line 26, page 78 line 21-30, example 6). Feces of commonly used laboratory mouse strains have both Gram-negative and Gram-positive bacteria. This is relevant to claims 5 and 6. Poncz further teaches their invention can be used to treat trauma, which includes common surgical procedure or settings that uses a sterile environment, anesthesia, antiseptic conditions (page 27 line 5-20). Antiseptic conditions is created by using antiseptics, which is a non-antibiotic antibacterial substance (instant specification paragraph 18). Poncz also teaches the method may further comprise treating said subject with a second therapy, such as an antibiotic (page 3 line 25-27). This is relevant to Claim 15. Poncz fails to teach the limitations that the method comprising administering PF4 to the subject can be used to treat bacterial infection caused by Staphylococcus aureus , antibiotic-resistant bacteria, or methicillin-resistant S. aureus , and the subject developed sepsis or peritonitis caused by S. aureus , as cited in Claims 7 -10, 12 and 14. However, Yeaman teaches infections due to antibiotic-resistant bacteria are increasing in frequency and severity and thus it would be desirable to provide peptides that are active against organisms that exhibit resistance to antibiotics, for use either independently or in combination to potentiate conventional antimicrobial agents (paragraphs 5 and 11). Antibiotic resistant pathogens currently of the greatest concern include methicillin resistant Staphylococcus aureus (MRSA) (paragraph 5). Yeaman also teaches the peptide PMP-2 is microbicidal against several different bacteria in vitro , such as E. coli (Gram-negative) and methicillin-resistant S. aureus (MRSA, Gram-positive) (paragraphs 3 and 118). The sequence of PMP-2 is provided in Seq ID NO.1, which is a fragment of rabbit PF4 precursor (see below). PNG media_image1.png 358 913 media_image1.png Greyscale It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Poncz and Yeaman, to administering PF4 to the subject to treat or inhibit a bacterial infection, where the bacterial infection, including sepsis and peritonitis, can be caused by S. aureus or antibiotic-resistant bacteria such as methicillin-resistant S. aureus (MRSA), because infections due to antibiotic-resistant bacteria are increasing in frequency and severity and thus it is desirable to develop methods to treat antibiotic-resistant bacteria, and PF4 fragment is microbicidal against MRSA in vitro . The motivation to do is in the teachings of Yeaman: it is desirable to provide peptides that are active against organisms that exhibit resistance to antibiotics such as MRSA because the severity and frequency of infections due to antibiotic-resistant bacteria are increasing (paragraphs 5 and 11), and PF4 fragment is microbicidal against MRSA in vitro . One would have a reasonable expectation of success in making the combination because the anti-bacteria effect of PF4 is dependent on its ability to bind with polyanionic bacteria as a cationic protein (Poncz page 3 line 6 and 18), and PF4 fragment is shown to inhibit the growth of MRSA in vitro (Yeaman paragraphs 3, 86 and 118). Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. Pertinent Art 07-96 AIA The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kowalska et al (Blood. 2007. 110(6):1903-1905) teaches in a lipopolysaccharide (LPS) survival model, hPF4 + mice had improved survival. hPF4 + mice are transgenic mice overexpressing human PF4. Krauel et al (Blood. 117 (4), pg. 1370-1378, Jan 2011) teaches PF4 binds to Gram-positive (such as S. aureus ) and Gram-negative bacteria (such as E. coli ) charge-dependently, and this binding induces antibodies with specificity for PF4/polyanion complexes (abstract, page 1372 section PF4 binding to bacteria). In addition, PF4 enhances the bacterial phagocytosis in vitro , and this mechanism can target a large variety of PF4-coated bacteria (Abstract, page 1373 section Biologic effects of anti-PF4/heparin antibodies). Lishko et al (J Biol Chem. 2018 Mar 14; 293 (18): 6869-6882) teaches PF4 augments phagocytosis of E coli in vitro by various types of macrophages (abstract, section PF4 augments phagocytosis of bacteria or plastic beads acting via Mac-1). Darveau et al (US 5,409,898 A) teaches a method of treating or inhibiting a bacterial infection (systemic infection by E. coli H16), or reducing the severity of a bacterial infection in a subject (neutropenic mouse), the method comprising administering PF4 (C-13 peptide, a fragment of PF4) to the subject. Although the C-13 peptide analogues or the cephalosporin (a beta-lactam antibiotic) does not improve mouse survival, administering both significantly improves mouse survival (column 26-28, section 11, table 4) . Conclusion Claims 1-2, 5-15 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN YANG whose telephone number is (571)272-6204. The examiner can normally be reached Monday - Thursday 8:00 am - 4:30 pm, Friday 8:00 am - 2:00 pm. 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 (571) 272-0857. 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. /TIAN YANG/Examiner, Art Unit 1674 /VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674 Application/Control Number: 18/252,171 Page 2 Art Unit: 1674 Application/Control Number: 18/252,171 Page 3 Art Unit: 1674
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