Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 5, 7-31, and 34-35 are cancelled.
Claims 1-4, 6, and 32-33 are pending.
Applicant’s election without traverse of Group I, claims 1-6, 17-22, 32-33, and 36-37 in the reply filed on 10/24/2025 is re-acknowledged. Upon further consideration, the species elections for one or more mutations of claims 5 and 17 (reciting the same mutations/residues) and for one or more mutations of claims 6 and 18 (reciting the same mutations/residues), as well as for claim 1 and its dependents or claim 17 and its dependents remain withdrawn in their entirety.
Claims 1-4, 6, and 32-33 are under examination on the merits.
Priority
This application is a 371 of PCT/US2021/027767, filed 04/16/2021, which claims benefit of U.S. Provisional Application No. 63/014,225, filed 04/23/2020.
Withdrawn Objections/Rejections
The objection to the specification is withdrawn in light of the 06/19/2026 amendment removing browser executable code. The objections to the form of claims 3 and 4 are withdrawn in light of the corrective claim amendments dated 06/19/2026. Any and all objections/rejections pertaining solely to claims 5, 17-22, or 36-37 are withdrawn as moot in light of the cancellation of these claims in the 06/19/2026 claim amendments. The rejections of the claims under 35 USC §112(b) are withdrawn in light of the clarifying claim amendments to claim 1 dated 06/19/2026. The rejections of the claims under 35 USC §103 are withdrawn and replaces with the rejections for nonobviousness as presented in this Office Action.
Maintained-Claim Interpretation
Tm onset and Tagg are parameters which are defined internally in the application (see for example, the instant specification at page 14, paragraphs 2-3), but are unusual parameters. These parameters can only be determined by a specific experimental set up in combination with the MicroCal VP-Capillary DSC Automated Analysis software 2.0 or UNnit® system to measure fluorescence in combination with the UNnit® analysis software (see for example, the instant specification at page 14). "The Tm onset” was defined as the temperature where specific heat (Cp) reached 2% of the maximum peak value. Further, "[t]he onset of aggregation (Tagg)” is defined as the first temperature at which the first derivative is larger than 0 (see for example, the instant specification at page 14, 3rd paragraph).
Therefore, recitations of measuring or otherwise using Tagg and Tm onset are being interpreted as reciting measurements obtained in accordance with the foregoing descriptions.
Recitations of measuring Tagg of the first and second antibody are being interpreted to mean measuring Tagg of the first antibody measured individually and of the second antibody measured individually (as is consistent with the Examples section of the instant specification).
Recitations of measuring Tm onset of the first and second antibody are being interpreted to mean measuring Tm onset of the first antibody measured individually and of the second antibody measured individually (as is consistent with the Examples section of the instant specification).
Recitations of comparing the Tagg and Tm onset of the first and second antibody are interpreted to means that the measured Tagg of the first antibody is compared to the measured Tagg of the second antibody and the measured Tm onset of the first antibody is compared to the measured Tm onset of the second antibody.
Note that recitations of “suitable for subcutaneous administration” are being interpreted to mean that the selected antibody has improved subcutaneous absorption and bioavailability (consistent with the constructive definition provided at paragraph 1 of the detailed description of page 3 of the instant specification). This notably does not specifically require that the antibody binds an intended target or has any effect (therapeutic or otherwise).
Claim 1 is being interpreted as a Markush group claim because the mutations are alternatively recited. Note that the MPEP provides that “any claim that recites alternatively usable members, regardless of format, should be treated as a Markush claim” (see MPEP §2117(I)).
Maintianed-35 U.S.C. 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6, and 32-33 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is directed to multiple judicial exceptions (comparison and selection steps (see for example, lines 1 and 7 of claim 1 and lines 1-2 of claim 17)). Furthermore the claim does not integrate said judicial exception in to a practical application and the claim does not recite additional elements that amount to significantly more than said judicial exception(s).
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to mental steps/abstract concepts of comparison and selection.
Claim 1 is directed to a method of selecting an antibody suitable for subcutaneous administration, the method comprising: measuring Tagg (temperature of aggregation onset) of a first and a second antibody that binds to the same target, measuring Tm onset (temperature of the unfolding onset) of the first and second antibody, comparing the Tagg and Tm onset of the first and second antibody; and selecting the first or second antibody that has a higher Tagg and/or Tm onset for subcutaneous administration, where sequencing and screening/selecting for the presence of enumerated residues/mutations is mere extrasolution activity. Claim 2 adds the further, generically recited step of measuring HpnIP and/or HIP (extrasolution activity). Claim 3 adds the further, generically recited step of measuring ka and/or %F (extrasolution activity). Claim 4 adds the further, generically recited step of measuring one or more enumerated PK parameters (extrasolution activity). Claim 6 adds the further, sequencing and screening/selecting for the presence of enumerated residues/mutations (extrasolution activity). Claim 32 adds the further implied step of determining/selecting for the a monoclonal antibody (extrasolution activity). Claim 33 adds the further implied step of determining/selecting for the an IgG1 or IgG4 isotype antibody (extrasolution activity). Thus, claims 2-6 and 32-33 incorporate and fail to remedy the deficiency of claim 1, from which they depend.
Regarding claim 1, the claim language reciting the judicial exception is found in exemplary lines 1 and 7 where explicit selection steps and implied steps of comparison are mental steps/abstract concepts which are judicial exceptions.
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 1 recites, “A method of selecting….” Therefore, the instant claim 1 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 1 includes explicit selection steps and one or more implied comparison steps which are mental steps/abstract concepts, which are judicial exceptions. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 1 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional, generic step(s) of measuring Tagg and/or Tm onset is/are mere extrasolution activity and the preamble is not given patentable weight where it does not breathe life and meaning into the claim (noting that, absent a definition for ‘suitable for subcutaneous administration’, the recitation only requires that the selected antibody be subcutaneously injectable or amendable to manipulation therefore). The implied step of sequencing and then screening for one or more of the enumerated residues/mutations is mere extra solution activity combined with the mental step of selection.
Therefore, the generic measuring steps amount to no more than mere data gathering steps and do not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claim fails to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in claim 1 (see for example, lines 1 and 7).
Therefore, the answer to prong 2B is “No” and the instant claim 1 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Claims 2-4, 6, and 32-33 only recited additional measurement/screening/selection criteria which do not integrate or add significantly more to the recitation of independent claim 1, from which they depend. Claims 2-4, 6, and 32-33 are accordingly included in this rejection.
Therefore, claims 1-4, 6, and 32-33 are rejected under 35 USC §101 as being directed towards patent ineligible mental steps/abstract concepts, failing to integrate or add substantially more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
Newly Necessitated by Amendment-Claim Rejections - 35 USC § 112
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 1-4, 6, and 32-33 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. This is a new matter rejection.
The examiner is unable to find support for the added limitation in claims 1 (incorporated via dependency by claims 2-4, 6, and 32-33) i.e., “measuring Tagg (temperature of aggregation onset) by differential scanning calorimetry of a first and a second antibody that binds to the same target, measuring Tm onset (temperature of the unfolding onset) by static light scattering of the first and second antibody”. This cannot be found anywhere in the instant disclosure. The instant specification only provides that a MicroCal VP-Capillary differential scanning calorimetry (DSC) system (Malvern Instruments Ltd., Malvern UK) was used for midpoint of temperature transition (Tm) measurement (see for example, pages 14 and 24). Likewise , the instant specification only provides that a combination of fluorescence data and static light scattering (SLS) or a combination of DSC and SLS were used to measure Tagg and Tm onset, but do not disclose measurement of Tm onset/Tm using SLS alone (see for example, pages 14-15 and 24 of the instant specification. Applicant is required to cancel the new matter in response to this office action.
Should applicant disagree with the examiner’s factual determination above, applicant should provide evidence that either or both of the provisional applications provide support for the invention now claimed in the manner required by 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. This could be accomplished, for example, by pointing to the specific page and line numbers within the specification, which disclose each limitation of the claimed invention.
Newly Necessitated by Amendment-Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perchiacca et al (Annu. Rev. Chem. Biomol. Eng. 2012. 3:263–86; 10.1146/annurev-chembioeng-062011-081052) in view of Genmab (WO 2019/155008 A1), Jacobs et al (Differential Scanning Calorimetry to Quantify Heat-Induced Aggregation in Concentrated Protein Solutions. Methods Mol Biol. 2019;2039:117-129. doi: 10.1007/978-1-4939-9678-0_9), AZO Materials (Dynamic Light Scattering as a Method for Understanding the Colloidal Stability of Protein Therapeutics, pub. 09/05/2014, obtained from: https://www.azom.com/article.aspx?ArticleID=11173), and Lu et al (WO2012021469A1).
Regarding claims 1 and 6, Perchiacca et al, while reviewing advances in antibody engineering to prevent aggregation of natively and non-natively folded antibody fragments, teach that antibody aggregation may be understood as condensation of folded or unfolded antibodies into reversible or irreversible antibody aggregates. Stresses such as elevated temperature or low pH can cause antibodies to partially or fully unfold if antibodies possess low thermodynamic or kinetic folding stability. The propensity of partially or fully unfolded antibodies to aggregate is determined by a competition between refolding (governed by intramolecular interactions) and aggregation (governed by intermolecular interactions). If intermolecular interactions between unfolded antibodies are sufficiently attractive (low colloidal stability), then unfolded antibodies condense into nonnative aggregates. Conversely, if intermolecular interactions between unfolded antibodies are repulsive or insufficiently attractive (high colloidal stability), then unfolded antibodies fold reversibly without aggregating (assuming that the refolding kinetics are not limiting). Elevated antibody concentrations, low temperatures, and related stresses can cause antibodies with low native colloidal stability to condense into native protein aggregates owing to attractive antibody self-interactions (see for example, the abstract at page 263 and pages 267-268). One way to impact kinetic stability may be to alter hydrophobicity (see for example, page 280). There is a long-felt need in the art to engineer antibodies resistant to aggregation in order to allow for the high doses/concentrations required for subcutaneous administration. The art has an understanding of certain aspects of antibody stability, such as thermodynamic folding stability (see for example, page 281).
Perchiacca et al do not explicitly teach measuring Tm onset or Tagg for a first and second antibody, comparing said parameters of said antibodies, and selecting the antibody with the higher of Tagg and Tm onset as suitable for subcutaneous administration.
However, Genmab, examining antibodies and routes of administration, teaches measurement of thermal stability by fluorescence/static light scattering. The fluorescence analysis provides the onset of unfolding temperature (T onset; understood to be a functional equivalent of the instantly recited ‘Tm onset’) and the melting temperature (Tm) values, both of which are generated from the BCM curves. The T onset provides the calculated temperature at which the protein begins to unfold. The Tm value is a transition midpoint of the protein from the folded state to the unfolded state. The UNit instrument ((Unchained Labs) measurement also provided SLS measurements for determining protein colloidal stability. The onset of aggregation temperature (Tagg) was determined from these data, which is the temperature at which the protein begins to aggregate (see for example, the abstract at the cover page and page 43).
The combined references do not teach measurement of Tagg using differential scanning calorimetry (DSC). DSC provides a range of information including the onset temperature for unfolding (Tm onset)
However, Jacobs et al teach that differential scanning calorimetry (DSC) is an important technique to measure the thermodynamics of protein unfolding (or folding) (see for example, the abstract at page 1). Aggregation resulting from heat-induced protein denaturation is perhaps the most well studied of these mechanisms. The thermodynamic parameters measured using DSC can provide useful information about intermolecular and intramolecular interactions between proteins in solution, which impact on the protein thermal stability and the nature of irreversible aggregation that often follows thermal denaturation. DSC is a method used in gaining insight into the heat-induced aggregation of biopharmaceuticals such as monoclonal antibodies, which can cause reduction in the efficacy of these treatments and immunogenicity (see for example, pages 2-3).
The combined references do not teach the use of static light scattering (SLS) to measure Tm onset.
However, AZO Materials teaches that turbidity or static light scattering (SLS) combined with thermal ramping have been traditionally employed as fast formulation screening tools for protein stability. These techniques determine the aggregation onset temperature Tm onset (see for example, page 4 at the Detecting Onset of Protein Aggregation section).
Note that the instant Application teaches 3 parent antibodies and 4 generated variants, including variant (1RE) having a lysine at residue 24 of LCDR1, a serine at residues 25 and 26 of LCDR1, a leucine, aspartic acid, and serine at positions 54, 55, and 56, respectively of :CDR2, and a phenylalanine at reside 96 of LCDR3{LCDRs1-3 having instant SEQ ID NOs: 1-2-3} and a glutamic acid at residue 61 of HCDR1, threonine at residue 30 of HCDR1 , and glycine at residue 65 of HCDR2{HCDRs1-3 having instant SEQ ID NOs: 7-5-8} (see for example, Table 1 at page 20 of the instant specification).
The combined references do not teach an antibody having one or more of the mutations selected from the group recited in the instant claim 1.
However, Lu et al teach an antibody having CDRs identical to the CDRs of the instant 1RE antibody (see for example, SEQ ID NO: 20 (LCVR of the mE8 antibody) of Lu et al comprising instant SEQ ID NOs: 1-2-3 and SEQ ID NO:21 (HCVR of the mE8 antibody) of Lu et al comprising instant SEQ ID NOs: 7-5-8, therefore having the same mutations and falling within the scope of the instant claims 1 and 6 (see for example, that that residues 24 of LCDR1 is lysine and residues 25-26 are serine in LCDR1 of Lu et al as shown in SEQ ID NO: 20 of Lu et al and residue 26 of HCDR1 is glycine, residue 27 of HCDR1 is tyrosine, residue 29 of HCDR1 is phenylalanine, residue 30 of HCDR1 is threonine, as shown in SEQ ID NO: 21 of Lu et al ). Lu et al teach that all of the antibodies were subcutaneously administered (see for example, Example 6 at page 17 and page 23 of Lu et al).
Alignment of SEQ ID NO: 20 of Lu et al and instant SEQ ID NOs: 1-2-3
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Alignment of SEQ ID NO: 21 of Lu et al and instant SEQ ID NOs: 7-5-8
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574
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Perchiacca et al teach that there is a long-felt need in the art to engineer antibodies resistant to aggregation (which may be caused by temperature stress or related to interactions of partially or fully unfolded proteins) in order to allow for the high doses/concentrations required for subcutaneous administration which would guide the artisan to select for antibodies with resistance to aggregation by selecting antibodies resistant to unfolding and/or with greater thermal stability (where a higher Tagg would have been understood as desirably selecting for antibodies capable of withstanding high temperatures before aggregation commenced). The artisan would have looked to the prior art to determine how to measure Tm onset (defined at the start of unfolding; see for example, page 34 of the instant specification) and the Tagg and would have found it obvious to use the measurement methods/means taught by Genmab as predictable in the method of antibody selection with a reasonable expectation of success. The artisan would have found measuring Tagg using DSC and Tm onset using SLS to be obvious, yielding no more than predictable results because Jacobs et al that DSC can be used to measure T onset (temperature at onset of thermal stress-induced unfolding/denaturation) is followed by aggregation (Tagg), the artisan would have found t obvious to use DSC as a measure of T onset acting as a general indicator of Tagg. From this, the artisan would have understood that measuring Tagg is an indirect way of approximately measuring Tm onset and measuring Tm onset is an indirect way of approximately measuring Tagg. Thus, where AZO materials teach that SLS is an art-known means to measure Tagg, the artisan would have found it obvious, yielding no more than predictable results to measure Tm onset (understood to roughly coincide with or near tag) using SLS. The artisan would have found it obvious to use art-known means for measuring Tagg and Tm onset in the method of Perchiacca et al in view of Genmab, said means of measurement being functional equivalents yielding no more than the predictable response of measuring Tagg and/or Tm onset. The artisan would have been motivated to look for structural components of antibodies suitable for subcutaneous administration, such as the residues/structures of the antibody of Lu et al to select for because the antibody of Lu et al is taught to be suitable for subcutaneous administration and has the instantly recited structure. Function (such as the properties associated with suitability for subcutaneous administration) derives, necessarily, from structure. The artisan would have been motivated to make and use the invention as claimed because it would have been obvious to take structural elements of antibodies known in the art to be suitable for subcutaneous administration and include those structures as part of a screening method for selecting antibodies suitable for subcutaneous administration. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Claim(s) 2-4 and 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perchiacca et al, Genmab, Jacobs et al, AZO Materials, and Lu et al as applied to claims 1 and 6 above, in view of Viola et al, (J Control Release 2018; 286:301-14; as cited and incorporated at page 1 of the instant specification) and Hoffman La Roche (WO2018/197533 A1).
Regarding claim 2, as mentioned above, Perchiacca et al teach that one way to impact kinetic stability may be to alter hydrophobicity (see for example, page 280).
The combined references do not explicitly teach a connection between hydrophobicity and or charge and subcutaneous use. measurement of heparin binding interaction potential (HpnIP) and/or hydrophobic interaction potential (HIP) .
However, Viola et al teach that stability and/or aggregation at the injection site impacts the absorption process in subcutaneous administration (see for example, column 2 of page 305). Viola et al further teach that the majority of the therapeutic peptide and proteins have an isoelectric point (pI) between 5 and 9. Particularly, mAbs have a pI ranging 7-9, which make them slightly positively charged at physiological subcutaneous pH. Negatively charged drugs are transported through the interstitial space faster than positive due to the negative charge present in ECM. In this case, electrostatic repulsion reduces the inter action between the drug and the ECM and promotes its interstitial transport by convection. On the other hand, positively charged mAbs might have a delayed subcutaneous absorption due to charge-charge inter actions between the subcutaneous space and them. In order to study the influence of the variable region (Fv) charge on the pharmacokinetics of antibodies, scientists modified two antibodies to have +3 and +5, and-4 charge compared with the original wild-type hosts. In one of them, +3 charge decreased the subcutaneous bioavailability to 31% compared with 60% of its parental counterpart, while the −4 charged antibody resulted in a enhance of 10%, presenting a SC bioavailability of 70%. Overall, it was observed in the same study that a charge-dependent trend in maximum serum concentrations and AUC (area under the curve) results with the positively charged antibodies having the lowest Cmax and AUC, and the negative variants presenting the highest values. Moreover, a study using subcutaneous rat ex vivo tissue was performed with the goal to analyze how antibody charge could affect subcutaneous bioavailability. Once again, they confirmed a trend, with more positively charged antibodies (pI 9.1) bounding more to rat subcutaneous tissue compared with the ones with less positive charge (pI 7.3) (see for example, page 306 with a focus on column 1).
Viola et al do not teach measurement of HIP using HIC or charge using HpnIP.
However, Hoffmann La Roche teaches that, to further elucidate the relationship of charge and heparin/FcRn-binding, variants of a parent/wild-type antibody (antibody no. 5) were synthesized covering the biophysical space of charges and hydrophobicities normally seen in antibody Fvs. Variants carrying positively charged patches showed strong heparin and FcRn column retention, which predicts fast clearance. Negatively charged patches showed weak heparin and FcRn column retention. Hoffman La Roche teach that "patchiness" or rather the influence of positively charged patches determines clearance in comparison to the pI which is a rather broad and therefore poor predictor of pharmacokinetics. Variant and wild-type antibody relative heparin column retention times were compared and where an antibody having a different systemic clearance relative to the parent antibody is selected a suitable for therapeutic use (see for example, pages 46-47).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Perchiacca et al teach that hydrophobicity impacts stability which impacts suitability for subcutaneous use. Viola et al further teach the importance of hydrophobicity/HIP and charge (patchiness of charge) as impacting subcutaneous absorption by impacting clearance and movement through the subcutaneous space. This would have motivated the artisan to measure charge and/or HIP to using a known method in the art, such as the heparin column retention timing of Hoffman La Roche, to select for an antibody having at least one of negative or not positive charge and/or lower HIP in order to select for an antibody more likely to move through the subcutaneous space, increasing subcutaneous absorption and therefore being more suitable for subcutaneous use. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 3, Viola et al teach measurement of the rate and extent of absorption and bioavailability after subcutaneous administration of art-known antibodies in a variety of animal models and teach that this is commonly done in order to investigate, for example, dosing, in the process of translating antibody research to an animal model and ultimately to human treatment (see for example, page 308).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would found it obvious to modify the teachings of Perchiacca et al to comprise measurement of the rate and extent of subcutaneous absorption and/or bioavailability between 2 comparative antibodies, such as the parent/wildtype and variant engineered antibody of Perchiacca et al and/or Viola et al because Perchiacca et al teach that there is a long-felt need in the art to engineer antibodies resistant to aggregation in order to allow for the high doses/concentrations required for subcutaneous administration (see for example, page 281) and Viola et al teach that such measurements aid in translating said antibodies into practical treatment of, for example, a human. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 4, it is noted that Viola et al teach measurement of pI and Cmax and comparison of these measurements between the parent antibody (antibody no. 5) and engineered variants (see for example, column 2 of page 305 and page 306 with a focus on column 1).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Perchiacca et al teach that there is a need to develop antibodies for subcutaneous administration which are resistant to aggregation (to handle associated high doses/concentration) and Viola et al teach factors which may be altered to optimize resistance to aggregation and suitability for subcutaneous administration. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 32-33, Perchiacca et al teach that several classes of human antibodies (IgG, IgA, and IgM) are known and share the same basic stricture, with monoclonal antibodies (mAbs) being well understood in the art (see for example, page 264), while both mAbs and fragments are known and understood to aggregate, the widespread use of antibodies and the ability to fully humanize them have motivated investigators to understand how to engineer antibodies to resist aggregation (see for example, page 264 bridging page 265). Viola et al additionally teach that many FDA-approved antibody treatments are human IgG1 or IgG4 antibodies (see for example, table 1 at page 303).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed to enhance suitability of known and common classes of therapeutic antibodies for less-invasive subcutaneous administration to enhance compliance and reduce healthcare costs, thereby meeting a long-felt need in the art (see for example, the abstract at page 301 and table 1 at page 303). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues for withdrawal of the rejections under 35 USC §101 because the claims recite active measurement steps which cannot practicably be performed in the human mind such that Applicant alleges the claims do not comprise any judicial exception (see pages 6-7 of the 06/19/2026 remarks).
Response: This is unpersuasive. First, the Examiner did not state that the claims fail to recite any active step, but rather explains that the active steps, being directed towards measurement and/or sequencing are extrasolution activity. Applicant does not present any argument related to this point for consideration. Applicant alleges that the claims do not comprise a judicial exception. This is not persuasive because it ignores the Examiner’s explanation of the presence of the selection steps being a mental process/abstract idea which is a judicial exception. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). There being no evidence, responsive argument for consideration, the rejections are maintained.
B. Applicant argues for withdrawal of the rejections under 35 USC §103 (see pages 7-10).
Response: The rejections for obviousness as presented in the previous office action have been withdrawn and replaced with the rejections presented in this Office Action to account for the new claim scope resulting from the 06/19/2026 claim amendments. It is noted that Applicant’s arguments regarding the withdrawn previous rejections discuss the references in isolation. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally, Applicant alleges surprising results, but does not provide sufficient, evidenced discussion of the results shown (Tables 5 and 6) relative to the cited prior art in combination to discuss why the results are surprising over the full claim scope in spite of the cited, combined prior art. Therefore, the rejections for obviousness as presented in this office action are maintained at this time.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bailly et al (MAbs, vol. 12, no. 1, pp. 1-28, doi: 10.1080/19420862.2020.1743053, publication date: 20200405) discloses (see for example pages 5 bridging 6) that methods such as DSF, nano-DSF, or differential scanning calorimetry (measuring Tonset and midpoint (Tm) temperatures of thermal unfolding transitions of proteins) can provide a method to rapidly rank antibody candidates. The putative link between protein conformational stability assessed by Tm, Tagg, and T onset measurements is considered potentially predictive or likely to be an indicator of long-term stability.
As previously cited, Fekete (Journal of Pharmaceutical and Biomedical Analysis 130 (2016) 3–18; http://dx.doi.org/10.1016/j.jpba.2016.04.004), Datta-Mannan et al (MABS
2020, VOL. 12, NO. 1, 1–14; https://doi.org/10.1080/19420862.2020.1770028), Cabreza et al (Mol Pharm. 2025 Sep 1;22(9):5504-5511. doi: 10.1021/acs.molpharmaceut.5c00523. Epub 2025 Aug 5), and ArgenX (WO 2013/175276 A1; citation 1 under the Foreign Patent Documents heading of the 09/02/2022 IDS) are deemed relevant.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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