DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 73, 74, 23-34, 36, 45, 46, 48 and 58, in the reply filed on 2/13/26 is acknowledged.
Claims 1, 4, 5, 6, 16 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Applicants are correct that claims 16 and 18 were intended to be n Group I.
Claim Rejections - 35 USC § 112-2nd paragraph
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 73, 74, 23-34, 36, 45, 46, 48 and 58 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 73 is vague and indefinite because it recites:
An in vitro method of identifying a subject colonized with Staphylococcus aureus (S. aureus) to be as responsive to an antibody or antigen- binding fragment thereof that binds to S. aureus alpha toxin (AT), the method comprising detecting S. aureus levels in a sample obtained from the subject, wherein a level of S. aureus that does not exceed a level of S. aureus that correlates to a PCR cycle threshold (Ct) value is indicative that the subject is responsive to the antibody or antigen-binding fragment thereof.
but provides no structure for the antibody to be used in the method and the phrase: be as responsive to an antibody or antigen- binding fragment thereof that binds to S. aureus alpha toxin (AT) is relative and vague and indefinite. The mere recitation of a name, i.e., antibody or antibody fragment that binds to AT, to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept, and then to determine a response that is “as responsive to that antibody or fragment” is confusing. The claim should provide any structural properties, such as the amino acid sequence of the antibody, which would allow for one to identify the antibody to be used without ambiguity. The mere recitation of a name does not adequately define the active ingredient. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow for one to identify what is being claimed.
Additionally, the method in itself is vague and confusing and is incomplete because it is unclear how one determines a subject is as responsive to a particular antibody by detecting the presence of the whole cell bacteria. The method claim appears to be missing essential method steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. There is no antibody detection step in the claim so it is unclear how detecting the level of S. aureus by PCR correlates directly to detecting the responsiveness of a patient to an antibody to S. aureus alpha toxin (ST). Appropriate clarification and/or correction is required.
Further, claim 73 is vague and indefinite because it is unclear what the PCR threshold value (Ct) may be. One cannot practice the invention without knowing the value. While a Ct (threshold cycle) value is an art recognized term in PCR technology, it is a relative measure (of the concentration of target in a PCR reaction) and many factors besides target concentration influence a given value of Ct. As such, the term as used in the present claims lacks clarity in not conveying a clear limiting technical feature on claimed subject matter using this term. Clearly for any such claim, without clear reference to a given threshold value (as recited in terms of for example concentration of bacteria), an essential feature is absent from the claim, and it cannot be seen as solving a problem defined along the lines of how to identify a subject as responsive to treatment with an S. aureus AT antibody. A designation in a patient sample of a concentration of S. aureus in terms of CFU/ml may be clearer. Appropriate clarification and/or correction is required.
The method steps of claim 73 are also confusing as for the dependent claims, it also is unclear if these PCR Ct values are determined before or after the antibody/antigen-binding fragment is administered since the method steps are not clear. Appropriate clarification and/or correction is required.
Claims 23 and 25 vague and indefinite due to the term “optionally” because it is unclear what the intended scope of is and the metes and bounds are not readily understood. See M’PEP 2173.05(h).
Claim 24 is vague and indefinite because it recites the PCR detect S. aureus protein A, yet the structure of protein A is not provided, nor is the structure of the reagent that detects it. The mere recitation of a name to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. The claim should provide any structural properties, such as the amino acid sequence of the antibody which binds the protein, which would allow for one to identify the protein without ambiguity. The mere recitation of a name does not adequately define the claimed protein. Appropriate clarification and/or correction is required.
Claim 58 is vague and indefinite because the sequence for the antibody or antigen binding fragment is not in the claim so it is unclear what these substitutions are in reference too. There is no reference sequence provided in the claim. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow for one to identify what is being claimed. Appropriate correction is required.
Claim Rejections - 35 USC § 112-Written Description
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 73, 74, 23-34, 36, 45, 46, 48 and 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant invention is drawn to:
An in vitro method of identifying a subject colonized with Staphylococcus aureus (S. aureus) to be as responsive to an antibody or antigen- binding fragment thereof that binds to S. aureus alpha toxin (AT), the method comprising detecting S. aureus levels in a sample obtained from the subject, wherein a level of S. aureus that does not exceed a level of S. aureus that correlates to a PCR cycle threshold (Ct) value is indicative that the subject is responsive to the antibody or antigen-binding fragment thereof.
The claims under rejection only recite a functional description for the active antibody. The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" 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 fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. Moreover, because the claims encompass a genus of variant species, 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 Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. For inventions 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'" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fires v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
In the instant case, Applicants have taught methods using antibody MEDI4893 which comprises:
Variable heavy chain (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3, a variable light chain (VL) CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:6.
Antibodies that bind to S.aureus Alpha toxin which comprise a VH of SEQ ID NO: 7 and VL of SEQ ID NO: 8 and an antibody which comprises a VH of SEQ ID NO: 9 and VL of SEQ ID NO: 10 are also recited.
No other antibody that binds S.aureus alpha toxin (AT) is disclosed.
"Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Because the claims encompass a genus of variant species, 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 Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. The Guidelines further state, "[f]or inventions in an unpredictable art, adequatewritten description of a genus which embraces widely variant species cannot beachieved by disclosing only one species within the genus'".accordingly, it follows that an adequate written description of a genus cannot beachieved in the absence of a disclosure of at least one species within the genus.
Therefore, absent a detailed and particular description of arepresentative number, or at least a substantial number of the members of thegenus of fragments and antibodies binding AT that have the ability to detect the “responsiveness” to an AT antibody from S.aureus under the conditions disclosed in the claims, the skilled artisan could not immediately recognize that Applicants were in possession of the claimed genus of antibodies at the time of filing. The scope of the claim includes numerous structural variants (i.e. fragments), and the genus is highly variant because a significant number of structural differences between genus members is permitted. The specification does not describe any members of the claimed genus by complete structure. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
There are no drawings or structural formulas disclosed of any of thesefragments or variants antibodies. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of antibodies or antigen binding fragments which bind AT and can treat colonized S.aureus, other than the antibody MEDI4893.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
Claim Rejections - 35 USC § 112- Enablement
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 73, 74, 23-34, 36, 45, 46, 48 and 58 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The instant claims recite, for example:
An in vitro method of identifying a subject colonized with Staphylococcus aureus (S. aureus) to be as responsive to an antibody or antigen- binding fragment thereof that binds to S. aureus alpha toxin (AT), the method comprising detecting S. aureus levels in a sample obtained from the subject, wherein a level of S. aureus that does not exceed a level of S. aureus that correlates to a PCR cycle threshold (Ct) value is indicative that the subject is responsive to the antibody or antigen-binding fragment thereof.
The essence of these claims may be said to amount to an in vitro method to identify a subject as responsive to treatment with an S. aureus AT antibody by determining a level of S. aureus in a sample from the patient. Clearly for any such claim, without clear reference to a given threshold value (as recited in terms of for example concentration of bacteria), an essential feature is absent from the claim, and it cannot be seen as solving a problem defined along the lines of how to identify a subject as responsive to treatment with an S. aureus AT antibody. Furthermore, even if a given threshold value was present, as previously indicated, the thrust of the invention, see example 5 of the application for instance, is that a better clinical outcome for treatment with antibody may be achieved in patients with a lower level of S. aureus infection than those with a higher level. However, the claims do not provided any direct correlation to responsiveness specifically to an antibody or antibody-fragment that binds to S.aureus alpha-toxin as it is only detecting the total number of S.aureus bacteria in a sample by PCR.
Additionally, if detection with an AT antibody was specifically added to the claims, It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and lightchain variable regions of a given antibody, each of which consists of three CDRswhich provide the majority of the contact residues for the binding of the antibodyto its target epitope. The amino acid sequences and conformations of each ofthe heavy and light chain CDRs are critical in maintaining the antigen bindingspecificity and affinity which is characteristic of the parent immunoglobulin. It isexpected that all of the heavy and light chain CDRs in their proper order and inthe context of framework sequences which maintain their required conformation,are required in order to produce a protein having antigen-binding function andthat proper association of heavy and light chain variable regions is required inorder to form functional antigen binding sites. Even minor changes in the aminoacid sequences of the heavy and light variable regions, particularly in the CDRs,may dramatically affect antigen-binding function.
MacCallum et al. J. Mol. Biol. (1996) 262,732-745, analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
De Pascalis et al. The Journal of Immunology (2002) 169, 3076-3084 demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (2003) BBRC 307, 198-205, which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
Vajdos et al. (2002) 320, 415-428, additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Holm et al. (2007) 44, 1075-1084 describes the mapping of an anti-cytokeratin antibody where although residues in the CDR3 of the heavy chain were involved in antigen binding unexpectedly a residue in CDR2 of the light chain was also involved (abstract). Chen et al. J. Mol. Bio. (1999) 293, 865-881. describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirelycomposed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866).
Wu et al. J. Mol. Biol. (1999) 294, 151-162. state that it is difficult to predict whichframework residues serve a critical role in maintaining affinity and specificity duein part to the large conformational change in antibodies that accompany antigenbinding (page 152 left col.) but certain residues have been identified as importantfor maintaining conformation.
The references demonstrate that an antibody must comprise all 6 CDRs inorder to maintain the antigen binding specificity and affinity which is characteristic of the immunoglobulin. Single VH or VL polypeptides would not bind antigen.
Additionally, The Office notes that the issue is make and use, not make and test to see if the skilled artisan could use. In short, the instant application encompasses a plethora of antibody variants possessing the ability to bind LF/LFIOE, and identifies some broad categories that might work, however, these descriptions, without moreprecise guidelines, amount to little more than "a starting point, a direction for further research." Genentech, 108 F.3d at 1366. See also Calgene, 188 F.3d at 1374 ("the teachings set forth in the specification provide no more than a 'plan' or 'invitation' for those of skill in the art to experiment practicing [the claimed invention]; they do not provide sufficient guidance or specificity as to how to execute that plan"); National Recovery Technologies, 166 F.3d at 1198 (stating that patent-in-suit "recognizes a specific need.., and suggests a theoretical answer to that need. It provides a starting point from which one of skill in the art can perform further research in order to practice the claimed invention, but this is not adequate to constitute enablement").
The instant specification does not describe the claimed invention in terms that will "enable any person skilled in the art.., to make and use" the invention commensurate in scope with the claims. At most, the specification will enable a person of ordinary skill in the art to attempt to discover how to practice the claimed invention.
CLAIM INTERPRETATION FOR PURPOSE OF ART REJECTIONS:
Claim 73 pertains to an in vitro method to identify a subject as responsive to treatment with an S. aureus AT antibody by determining that the level of S. aureus in a sample from the patient correlates with a given (unspecified) PCR Ct value. In claim 74, the Ct value is given as 29. Given the clarity issues surrounding reference to a Ct value, the essence of these claims may be said to amount to an in vitro method to identify a subject as responsive to treatment with an S. aureus AT antibody by determining a level of S. aureus in a sample from the patient. Clearly for any such claim, without clear reference to a given threshold value (as recited in terms of for example concentration of bacteria), an essential feature is absent from the claim, and it cannot be seen as solving a problem defined along the lines of how to identify a subject as responsive to treatment with an S. aureus AT antibody. Furthermore, even if a given threshold value was present, as previously indicated, the thrust of the invention, see example 5 of the application for instance, is that a better clinical outcome for treatment with antibody may be achieved in patients with a lower level of S. aureus infection than those with a higher level. This would be obvious to one of ordinary skill in the art. Accordingly, any in vitro claim based that measures S. aureus levels in a sample would appear to read on the instant claims. The idea that a sample that has more S. aureus bacteria present would be harder to treat and less responsive would appear to be obvious to one of ordinary skill in the art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 73, 74, 23-34 and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bruno et al (Intensive Care Med. Berlin, DE. 44(11): 1787-1796. October 18, 2018; provided by Applicants), Bruno et al (WO 2017/075188 A2; provided by Applicants), Hua et al (Antimicrobial Agents and Chemotherapy. 59(8): 4526-4532. August 2015; provided by Applicants) and Chaparro et al (WO 2013/093693; provided by Applicants).
Bruno et al is a disclosure of a phase 1/2a clinical trial with the fully human monoclonal IgG1 lambda antibody AR-301 in ICU patients with severe S.aureus pneumonia. In terms of clinical effect, ventilation duration of patients given antibody was shorter as compared to placebo, and there was a ‘trend’ towards better and faster eradication at day 28 of treatment. While nothing in Bruno specifically recites a sample obtained from the subject using PCR, this is not a limiting technical feature in the claim (for example, clearly defining a particular patient group to be treated). Reference to the sample not exceeding a level of S.aureus correlating to a non-specified PCR Ct value is not equally limiting.
Bruno WO2017 is a prior disclosure by the applicant of the present application, and pertains in particular to the preferred antibody binding S.aureus alpha toxin (MEDI4893) of the present application, and its use in the treatment /prevention of infection. Effects included those pertaining to pneumonia, and included is the use of the antibody at the preferred dosage used in the present application.
Hua equally discloses the preferred antibody MEDI4893, and its ability to protect both normal and immunocompromised mice from S.aureus pneumonia. After treatment with antibody, mice were challenged with 2 x 107 CFU of bacteria. While nothing in Hua specifically recites a sample obtained from the subject using PCR, this is not a limiting technical feature in the claim (for example, clearly defining a particular patient group to be treated). Reference to the sample not exceeding a level of S.aureus correlating to a non-specified PCR Ct value is not equally limiting.
Chapparo et al discloses the S. aureus alpha-toxin antibody DF1.1 delivered ip to mice prior to bacterial challenge. Mortality rates were studied, and it was found that challenge with 10° CFUs was more lethal than 3.16 x 10° CFUs, which in turn was more lethal than 108 or 3.16 x 10’ CFUs. While nothing in the reference specifically recites a sample obtained from the subject using PCR, this is not a limiting technical feature in the claim (for example, clearly defining a particular patient group to be treated). Reference to the sample not exceeding a level of S.aureus correlating to a non-specified PCR Ct value is not equally limiting.
The teachings of Bruno et al, Bruno et al (WO 2017), Hua and Chaparro et al are set forth above. The instant claims recite that the level of S.aureus does not exceed a value correlating to a Ct, and more specifically that the value is Ct 29 which corresponds to a sample concentration of S.aureus that does not exceed 1700 colony forming units (CFU)/ml of S.aureus, were not particularly exemplified by these references.
However, as stated in the 112, second paragraph rejection above, while a Ct (threshold cycle) value is per se a recognized term in PCR technology, it is equally recognized that it is a relative measure (of the concentration of target in a PCR reaction), and many factors besides target concentration influence a given value of Ct. As such, the term as used in the present claims lacks clarity in not conveying a clear limiting technical feature on subject matter using this term.
In Example 5 of the instant application, it has been shown that in a treatment of mechanically ventilated S. aureus ICU patients with antibody MEDI4893 (suvratoxumab), those with a Ct value greater than 29 (corresponding to low S. aureus colonization) had a statistically significant relative risk reduction of 67%, whilst those with a Ct value less than 29 had a non-significant relative risk reduction of 2.5%. This indicates that a better clinical outcome may be achieved in patients with a lower level of S.aureus infection.
It would have been obvious to one of ordinary skill in the art that a better clinical outcome would be expected in patients with a lower level of bacterial infection. Chaparro et al disclose in Table 5 on page 87 that with regard to mortality rates in animals challenged with various bacterial levels, challenge with 109 CFUs was more lethal than 3.16 X 108 CFUs, which in turn was more lethal than 108 or .16 X 107 CFUs.
Clearly for any of the claims, without clear reference to a given threshold value (as recited in terms of for example concentration of bacteria), an essential feature is absent from the claim, and it cannot be seen as solving a problem defined along the lines of how to identify a subject as responsive to treatment with an S.aureus AT antibody. Furthermore, even if a given threshold value was present, as previously indicated, the thrust of example 5 of the instant application is that a better clinical outcome for treatment with antibody may be achieved in patients with a lower level of S.aureus infection than those with a higher level as was indicated in the Chapparo et al reference. Accordingly, any in vitro claim based on present claim 73 and reflecting such purported contribution to the state of the art, would have been obvious to one of ordinary skill in the art. The dependent claims refer specifically to the different sample types and these are typical known sites to drawn samples for detection of S.aureus infection.
Correspondence regarding this application should be directed to Group Art Unit 1645. Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center located in Remsen. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15,1989). The Group 1645 Fax number is 571-273-8300 which is able to receive transmissions 24 hours/day, 7 days/week.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Thomas Visone, can be reached at (571) 270-0684.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/Primary Examiner, Art Unit 1645 4/27/26
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